NM_000218.3:c.1760C>T

Variant names:

• chr11-2778003-C-T
• rs120074189
• NM_000218.3:c.1760C>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 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:8 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 coiled_coil_region (size 36) in uniprot entity KCNQ1_HUMAN there are 27 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 chr11-2778003-C-G is described in Lovd as [Pathogenic].
• 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 rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1760C>T	p.Thr587Met	missense_variant	Exon 15 of 16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1760C>T	p.Thr587Met	missense_variant	Exon 15 of 16	1	NM_000218.3	ENSP00000155840.2

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:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Dec 08, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Jan 24, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1, PP3, PM2, PM3, PM6, PS3, PS4 -

Long QT syndrome Pathogenic:2

Dec 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). 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: 11162126, 19959132, 20348026). For these reasons, this variant has been classified as Pathogenic. -

-

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome 1 Pathogenic:1

Aug 01, 2023

Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jervell and Lange-Nielsen syndrome 1 Pathogenic:1

Feb 19, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

KCNQ1-related disorder Pathogenic:1

May 07, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The KCNQ1 c.1760C>T variant is predicted to result in the amino acid substitution p.Thr587Met. This variant was reported in numerous individuals with Long QT syndrome (Schwartz et al. 2021. PubMed ID: 34505893; Westphal et al. 2020. PubMed ID: 32383558; Yamashita et al. 2001. PubMed ID: 11162126). Functional studies suggest this variant compromises the structure and function of Kv7 potassium ion channels, which are important in cardiac and other tissues (Howard et al. 2007. PubMed ID: 17329207). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Cardiovascular phenotype Pathogenic:1

May 31, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). 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. -

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: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
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;.;.;.
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;