rs199472760

Positions:

• chr11-2583537-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000155840.12(KCNQ1):​c.1024C>T​(p.Leu342Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. L342H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ1 ENST00000155840.12 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 3.04

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 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, 8 uncertain in ENST00000155840.12
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-2583538-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 405269.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 11-2583537-C-T is Pathogenic according to our data. Variant chr11-2583537-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 52932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2583537-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1024C>T	p.Leu342Phe	missense_variant	7/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1024C>T	p.Leu342Phe	missense_variant	7/16	1	NM_000218.3	ENSP00000155840	P1
KCNQ1	ENST00000335475.6	c.643C>T	p.Leu215Phe	missense_variant	7/16	1		ENSP00000334497
KCNQ1	ENST00000496887.7	c.763C>T	p.Leu255Phe	missense_variant	8/16	5		ENSP00000434560
KCNQ1	ENST00000646564.2	c.580C>T	p.Leu194Phe	missense_variant	3/11			ENSP00000495806

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 07, 2023	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 342 of the KCNQ1 protein (p.Leu342Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of long QT syndrome (PMID: 9386136, 24217263, 26675252; Invitae). ClinVar contains an entry for this variant (Variation ID: 52932). 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: 9312006). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 06, 2011

This missense change is denoted Leu342Phe (aka L342F) at the protein level and c.1024 C>T at the cDNA level. The Leu342Phe mutation in the KCNQ1 gene has been published previously in association with LQTS (Donger C et al., 1997, Berge K et al.,2008). Donger et al. (1997) first reported Leu342Phe in five individuals in one family, one of whom was considered symptomatic by having the first episode of syncope before the age of 10. The same study did not detect Leu342Phe in 100 controls (Donger C et al., 1997). Leu342Phe, located in the S6 region of the protein, was subsequently described in three members of one family with LQTS (Berge et al, 2008). Mutations in neighboring residues (Ala341Glu, Ala341Gly, Ala341Val, Pro343Arg, Pro343Leu, Pro343Ser) have also been reported in association with LQTS, further supporting the functional importance of this region of the protein. Furthermore, Leu342Phe was not observed in up to 400 control alleles of Caucasian ethnic background tested at GeneDx, indicating it is not a common benign polymorphism in this population. The variant is found in LQT panel(s). -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 21, 2016

The p.L342F variant (also known as c.1024C>T), located in coding exon 7 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 1024. The leucine at codon 342 is replaced by phenylalanine, an amino acid with highly similar properties. This variant has been reported in several long QT syndrome (LQTS) cohorts (Donger C et al. Circulation. 1997;96:2778-81; Berge KE et al. Scand J Clin Lab Invest. 2008;68:362-8; Kapplinger JD et al. Heart Rhythm. 2009;6:1297-303; Stattin EL et al. BMC Cardiovasc Disord. 2012;12:95; Haugaa KH et al. Heart Rhythm, 2013 Dec;10:1877-83; Hedley PL et al. Cardiovasc J Afr. 2013;24:231-7; Izumi G et al. Pediatr Cardiol, 2016 Jun;37:962-70). In functional in vitro analyses, this variant has been shown to decrease potassium channel current density (Chouabe C et al. EMBO J. 1997;16:5472-9). 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. -

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:18752142;PMID:19716085). 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	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Benign	0.57	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.1	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.7	D;.;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0	D;.;D
Polyphen		1.0	D;.;D
Vest4		0.96
MutPred		0.90		Loss of catalytic residue at L342 (P = 0.1072);.;.;
MVP		0.99
MPC		1.2
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.91
gMVP		0.95

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

Other links and lift over

dbSNP: rs199472760; hg19: chr11-2604767; COSMIC: COSV50101012;