11-2587581-G-T

Position:

• chr11-2587581-G-T

Variant summary

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

The NM_000218.3(KCNQ1):​c.1140G>T​(p.Arg380Ser) 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. R380G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 1.34

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 helix (size 25) in uniprot entity KCNQ1_HUMAN there are 25 pathogenic changes around while only 1 benign (96%) 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 chr11-2587579-A-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 11-2587581-G-T is Pathogenic according to our data. Variant chr11-2587581-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 52964.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2587581-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1140G>T	p.Arg380Ser	missense_variant	9/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1140G>T	p.Arg380Ser	missense_variant	9/16	1	NM_000218.3	ENSP00000155840	P1
KCNQ1	ENST00000335475.6	c.759G>T	p.Arg253Ser	missense_variant	9/16	1		ENSP00000334497
KCNQ1	ENST00000496887.7	c.783G>T	p.Arg261Ser	missense_variant	9/16	5		ENSP00000434560
KCNQ1	ENST00000646564.2	c.600G>T	p.Arg200Ser	missense_variant	4/11			ENSP00000495806

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes

Aug 01, 2023

- -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 14, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg380 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been observed in individuals with KCNQ1-related conditions (PMID: 19841298; Invitae), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 24190995, 26344792). 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. ClinVar contains an entry for this variant (Variation ID: 52964). This missense change has been observed in individual(s) with long QT syndrome (PMID: 15840476, 26344792; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 380 of the KCNQ1 protein (p.Arg380Ser). -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 20, 2019

The p.R380S variant (also known as c.1140G>T), located in coding exon 9 of the KCNQ1 gene, results from a G to T substitution at nucleotide position 1140. The arginine at codon 380 is replaced by serine, an amino acid with dissimilar properties. This alteration has been detected in unrelated individuals reported to have long QT syndrome (Tester DJ et al. Heart Rhythm. 2005;2:507-17; Giudicessi JR et al. Circ Cardiovasc Genet. 2012;5:519-28; Zhou H et al. Cardiol Young. 2016;26:754-63). In vitro studies have reported this alteration to result in altered ion channel function and ATP sensitivity (Li Y et al. Proc Natl Acad Sci. U.S.A. 2013;110:18922-7; Zhou H et al. Cardiol Young. 2016;26:754-63). In addition, another alteration affecting this amino acid (p.R380G, c.1138A>G) has been reported in association with prolonged QTc interval (Schwartz PJ et al. Circulation, 2009 Nov;120:1761-7). 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:15840476;PMID:19841300). 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	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.;.
Eigen	Benign	0.16
Eigen_PC	Benign	0.0087
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.8	D;.;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0	D;.;D
Polyphen		1.0	D;.;D
Vest4		0.99
MutPred		0.86		Loss of MoRF binding (P = 0.0469);.;.;
MVP		0.98
MPC		1.0
ClinPred		1.0	D
GERP RS		1.8
Varity_R		0.98
gMVP		0.98

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: rs199472771; hg19: chr11-2608811;