11-2778003-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 NM_000218.3(KCNQ1):c.1760C>T(p.Thr587Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,444 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T587R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 3.41

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 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain 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 chr11-2778003-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1037124.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 11-2778003-C-T is Pathogenic according to our data. Variant chr11-2778003-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2778003-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.1760C>T	p.Thr587Met	missense_variant	15/16	ENST00000155840.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1760C>T	p.Thr587Met	missense_variant	15/16	1	NM_000218.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461444 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727056

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 07, 2024	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 587 of the KCNQ1 protein (p.Thr587Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with long QT syndrome (PMID: 9799083, 10024302, 11162126, 15234419, 18752142, 20487114, 24217263). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 3138). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 11162126, 19959132, 20348026). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -

Long QT syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes

Aug 01, 2023

- -

Jervell and Lange-Nielsen syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 19, 1999

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 08, 2017

The T587M variant has been published in many individuals of various ethnic backgrounds with LQTS, and the variant has segregated with disease in family studies (Itoh et al., 1998; Yamashita et al., 2001; Chen et al., 2003l; Shimizu et al., 2004; Giudicessi et al., 2009; Hedley et al., 2013). Furthermore, there have been at least two reports of compound heterozygous individuals, harboring the T587M variant and an additional KCNQ1 variant, with Jervell and Lange-Nielsen Syndrome. In testing parents, Neyroud et al. (1999) was able to conclude that the T587M variant was de novo on the paternal allele in an affected child, while the second KCNQ1 variant was maternally inherited. The T587M variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T587M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where only amino acids with similar properties to threonine are tolerated across species, which does not include methionine. In silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, in vivo functional analyses showed that, in the presence of the T587M variant, protein trafficking was adversely affected (Yamashita et al., 2001; Biliczki et al., 2009; Hayashi et al., 2010). More specifically, the KCNQ1-encoded potassium channel is unable to properly localize to the cell membrane and delayed rectifier current, both KCNQ1- and KCNH2-associated, are reduced, which the authors postulate may explain the more severe LQTS phenotypes reported in some individuals with this variant. Lastly, T587M is located in the coiled coil domain that mediates tetramerization, where other pathogenic or likely pathogenic missense variants in nearby residues (G589D, A590T, R591C, R591H) have been reported in the Human Gene Mutation Database in association with LQTS (Stenson et al., 2014). -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 2019

The p.T587M pathogenic mutation (also known as c.1760C>T), located in coding exon 15 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 1760. The threonine at codon 587 is replaced by methionine, an amino acid with some similar properties. This alteration has been described in association with long QT syndrome in a number of individuals from various ethnic groups (Itoh T et al. Hum Genet. 1998;103(3):290-4; Yamashita F et al. J Mol Cell Cardiol. 2001;33(2):197-207; Berge KE et al. Scand J Clin Lab Invest. 2008;68(5):362-8; Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303; Furushima H et al. J Cardiovasc Electrophysiol. 2010;21(10):1170-3; Giudicessi JR et al. Circ Cardiovasc Genet. 2012;5(5):519-28; Hedley PL et al. Cardiovasc J Afr. 2013;24(6):231-7). In one case, this alteration was reported to occur de novo in an individual with Jervell and Lange-Nielsen syndrome who also was reported to carry a KCNQ1 splice alteration in trans (Neyroud N et al. Circ Res. 1999;84(3):290-7). Studies by different groups have suggested this alteration to result in abnormal protein trafficking, and in vitro studies have reported this alteration to result in non-functional channels (Yamashita F et al. J Mol Cell Cardiol. 2001;33(2):197-207; Biliczki P et al. Heart Rhythm. 2009; 6(12):1792-801). Furthermore, this alteration was reported to affect KCNH2 protein localization, and to not properly induce current amplitude as compared to wild type protein (Biliczki P et al. Heart Rhythm. 2009;6(12):1792-801; Hayashi K et al. Heart Rhythm. 2010;7(7):973-80). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

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:9799083;PMID:10024302;PMID:11162126;PMID:12702160;PMID:15840476;PMID:17329209;PMID:18752142;PMID:19716085;PMID:19841300;PMID:19959132;PMID:15234419;PMID:17329207;PMID:9386136;PMID:20348026). 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	Uncertain	0.43
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.42
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;.;.;.
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.075
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M;.;.;.
MutationTaster	Benign	0.98	A;A
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.7	D;.;D;.
REVEL	Pathogenic	0.83
Sift	Benign	0.082	T;.;T;.
Sift4G	Benign	0.19	T;.;T;.
Polyphen		0.98	D;.;D;.
Vest4		0.84
MutPred		0.83		Gain of MoRF binding (P = 0.0872);.;.;.;
MVP		0.97
MPC		1.2
ClinPred		0.99	D
GERP RS		2.2
Varity_R		0.21
gMVP		0.93

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: rs120074189; hg19: chr11-2799233;