11-2571394-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000218.3(KCNQ1):c.674C>T(p.Ser225Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000343 in 1,459,266 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 (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11O:1

Conservation

PhyloP100: 5.75

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 12) in uniprot entity KCNQ1_HUMAN there are 13 pathogenic changes around while only 0 benign (100%) in NM_000218.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.984

PP5

Variant 11-2571394-C-T is Pathogenic according to our data. Variant chr11-2571394-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2571394-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3 link	c.674C>T	p.Ser225Leu	missense_variant	Exon 4 of 16	ENST00000155840.12	NP_000209.2	P51787-1Q96AI9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KCNQ1	ENST00000155840.12 link	c.674C>T	p.Ser225Leu	missense_variant	Exon 4 of 16	1	NM_000218.3	ENSP00000155840.2	P51787-1
KCNQ1	ENST00000335475.6 link	c.293C>T	p.Ser98Leu	missense_variant	Exon 4 of 16	1		ENSP00000334497.5	P51787-2
KCNQ1	ENST00000496887.7 link	c.413C>T	p.Ser138Leu	missense_variant	Exon 5 of 16	5		ENSP00000434560.2	E9PPZ0
KCNQ1	ENST00000646564.2 link	c.478-12041C>T		intron_variant	Intron 2 of 10			ENSP00000495806.2	A0A2R8YEQ9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000121

AC:

AN:

248308

Hom.:

AF XY:

0.0000223

AC XY:

AN XY:

134824

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:

0.0000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000343

AC:

AN:

1459266

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

726064

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:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long QT syndrome

Pathogenic:3

Aug 31, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces serine with leucine at codon 225 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have shown this variant has a dominant-negative effect on potassium channel current and changes the activation and deactivation rates of the channel (PMID: 11087258, 19590188, 21451124, 22456477). This variant has been reported in many individuals affected with long QT syndrome or referred for long QT syndrome genetic testing (PMID: 9927399, 10973849, 14678125, 15466642, 15840476, 17470695, 19716085, 19841300, 21451124, 22456477, 22727609, 22949429, 23130128, 24606995, 29925740). This variant has been identified in 3/248308 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Apr 21, 2016

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 225 of the KCNQ1 protein (p.Ser225Leu). This variant is present in population databases (rs199473456, gnomAD 0.003%). This missense change has been observed in individuals with long QT syndrome (PMID: 9927399, 10973849, 15840476, 17470695, 19716085, 22727609, 22949429, 23130128, 24606995). ClinVar contains an entry for this variant (Variation ID: 53083). 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) 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: 11087258, 19590188, 21451124, 22456477). For these reasons, this variant has been classified as Pathogenic. -

Long QT syndrome 1

Pathogenic:2

May 02, 2019

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 20, 2020

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital long QT syndrome

Pathogenic:1Other: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:9927399;PMID:10973849;PMID:14678125;PMID:15466642;PMID:15840476;PMID:19590188;PMID:19716085;PMID:19841300;PMID:17999538;PMID:17470695;PMID:22456477). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Oct 27, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ser225Leu variant in KCNQ1 has been reported in >15 individuals with long QT syndrome (LQTS) or referred for LQTS genetic testing (Priori 1999 PMID: 9927399, Splawski 2000 PMID: 10973849, Tester 2005 PMID: 15840476, Kapplinger 2009 PMID: 19716085, Andrsova 2012 PMID: 22727609, Giudicessi 2012 PMID: 22949429, Christiansen 2014 PMID: 24606995). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 53083) and has been identified in 0.003% (1/30612) of South Asian and 0.001% (2/112392) European chromosomes by gnomAD (http://gnomad.broadinstitute.org/, v.2.1.1). In vitro functional studies provide some evidence that the p.Ser225Leu variant may impact protein function, potentially through a dominant negative mechanism (Bianchi 2000 PMID: 11087258, Henrion 2009 PMID: 19590188, Barsheshet 2012 PMID: 22456477) and computational prediction tools and conservation analysis suggest that the p.Ser225Leu variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, the p.Ser225Leu variant meets criteria to be classified as likely pathogenic for autosomal dominant LQTS. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PS3_Supporting, PP3. -

Beckwith-Wiedemann syndrome;C1837014:Atrial fibrillation, familial, 3;C1865019:Short QT syndrome type 2;C4551509:Jervell and Lange-Nielsen syndrome 1;C4551647:Long QT syndrome 1

Pathogenic:1

Nov 23, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

KCNQ1-related disorder

Pathogenic:1

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported in multiple individuals and families affected with long QT syndrome (PMID: 9927399, 10973849, 15840476, 17470695, 19716085, 22949429, 23130128). Experimental studies have shown that this missense change has a dominant-negative effect on channel activity (PMID: 11087258, 19590188, 21451124, 22456477). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.001% (3/248308) and thus is presumed to be rare. The c.674C>T (p.Ser225Leu) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.674C>T (p.Ser225Leu) variant is classified as Pathogenic. -

not provided

Pathogenic:1

Oct 13, 2014

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Likely 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.Ser225Leu This variant has been reported in at least 11 unrelated individuals with LQTS and as many as 13 total subjects. There is no segregation data available on the variant. Priori et al (1999) first identified the variant in an Italian family where 1 member had a LQTS diagnosis and 2 first degree relatives were found to be carriers but did not have a clinical diagnosis. Splawski et al (2000) reported 2 families with p.S225L and LQTS. One family is from the US and the other is from Italy, thus we cannot assume that this family is a separate new case from the Priori et al family. Three years later the same author group reports the presence of the variant in 2/294 cases derived from the International Long QT Registry (Zareba et al). Based on the sample source and author group it is highly likely that these 2 cases are the same as the cases in Splawskis paper. Choi et al (2004) report that the variant was identified in 1/388 unrelated patients sent to Mayo for LQTS genetic testing between August 1997 and May 2003. The average QTc of the cohort was 482ms. The individual was a 12 yo male whose arrhythmic event was triggered by swimming. Tester et al (2005) reported the variant in 3/541 unrelated cases sent to Mayo for testing between August 1997 and July 2004. One of these cases likely overlaps with Choi et al. Moss et al (2007) reported the variant in 13/600 individuals with LQT. It cannot be assumed that these 13 subjects are not related. Kapplinger et al (2009) reported 8 unrelated cases with the variant out of 2500 patients referred to Familion for LQTS genetic testing between May 2004 and October 2008. Recently Medlock et al (2012) re-tested all LQTS subjects who were found to be genotype negative in previous studies (n=269) and identified 1 additional new case with p.S225L variant. Thus bringing the total to 11 unrelated cases. The Couderc et al (2012) publication mentions p.S225L variant but the patient population had previously been genotyped thus no new cases can be added. This is a non conservative amino acid change with a polar Serine replaced with a nonpolar Leucine. In silico analysis predict the amino acid replacement to be damaging /possibly damaging to resulting protein function (SIFT/PolyPhen). Additional variants (R231C, R231H) in nearby codons have been reported in association with LQTS thus indicating a functional significance of this region of the KCNQ1 gene. Henrion et al (2009) demonstrated that xenopus oocytes with the p.S225L variant in KCNQ1 had altered voltage dependencies for activation and deactivation compared to wildtype oocytes. Priori et al (1999) did not identify the variant in 100 presumably healthy controls. Kapplinger et al (2009) report that the variant was absent in 1300 presumably healthy controls (47% Caucasian, 26% African American, 11% Hispanic, 10% Asian, and 6% unknown/other). In total the variant is absent if 1400 presumably healthy individuals. The variant is listed in dbSNP with the rs # 199473456; however there is no allele frequency data available. It is not listed in 1000Genomes. There is no variation at codon 225 in the NHLBI ESP, which currently includes variant calls from ~6500 individuals (as of November 29th 2012). -

Cardiovascular phenotype

Pathogenic:1

Feb 26, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S225L variant (also known as c.674C>T), located in coding exon 4 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 674. The serine at codon 225 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in multiple individuals with long QT syndrome (LQTS) (Priori SG et al. Circulation. 1999;99(4):529-33; Tester DJ et al. Heart Rhythm. 2005;2(5):507-17; Moss AJ et al. Circulation. 2007;115(19):2481-9; Itoh H et al. Heart Rhythm. 2010;7(10):1411-8; Andrsova I et al. J Electrocardiol. 2012;45(6):746-51; Christiansen M et al. BMC Med. Genet. 2014;15:31). This alteration has also been shown to have an impact on protein function (Bianchi L et al. Am. J. Physiol. Heart Circ. Physiol. 2000;279(6):H3003-11; Henrion U et al. Cell. Physiol. Biochem. 2009;24(1-2):11-6; Jons C et al. Sci Transl Med. 2011;3:76ra28; Liin SI et al. Elife. 2016;5:e20272). 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

Nov 20, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

.;D;.

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.85

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.4

.;L;.

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-5.9

D;D;D

REVEL

Pathogenic

0.87

Sift

Benign

0.031

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

0.99

.;D;.

Vest4

0.98, 0.98

MutPred

0.85

.;Gain of helix (P = 0.0078);.;

MVP

0.97

MPC

0.94

ClinPred

0.99

GERP RS

4.3

Varity_R

0.92

gMVP

0.96

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