11-2776032-C-T

Position:

• chr11-2776032-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_000218.3(KCNQ1):​c.1663C>T​(p.Arg555Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000424 in 1,416,324 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. R555H) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11 O:1
• Conservation: PhyloP100: 3.59

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 16 ACMG points.

• PM1: In a region_of_interest Interaction with KCNE1 C-terminus (size 37) in uniprot entity KCNQ1_HUMAN there are 36 pathogenic changes around while only 1 benign (97%) in NM_000218.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-2776033-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 11-2776032-C-T is Pathogenic according to our data. Variant chr11-2776032-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2776032-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.1663C>T	p.Arg555Cys	missense_variant	13/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1663C>T	p.Arg555Cys	missense_variant	13/16	1	NM_000218.3	ENSP00000155840.2
KCNQ1	ENST00000335475.6	c.1282C>T	p.Arg428Cys	missense_variant	13/16	1		ENSP00000334497.5
KCNQ1	ENST00000496887.7	c.1306C>T	p.Arg436Cys	missense_variant	13/16	5		ENSP00000434560.2
KCNQ1	ENST00000646564.2	c.1123C>T	p.Arg375Cys	missense_variant	8/11			ENSP00000495806.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.0000111 AC: 2 AN: 179696 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 95188

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: 0.00

Gnomad FIN exome AF: 0.0000623

Gnomad NFE exome AF: 0.0000133

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000424 AC: 6 AN: 1416324 Hom.: 0 Cov.: 33 AF XY: 0.00000286 AC XY: 2 AN XY: 699948

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: 0.0000201

Gnomad4 NFE exome AF: 0.00000459

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ExAC AF: 0.0000172 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Region Ostergotland	Jul 13, 2021	PS3, PS4, PP1, PP3_moderate -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 04, 1997	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes	Aug 01, 2023	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 25, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 12, 2023	Reported in association with LQTS in multiple individuals referred for genetic testing at GeneDx and in the published literature (PMID: 9386136, 12877697, 15840476, 19716085, 26669661); Segregates with disease in many affected individuals from several families in the published literature, and observed to result in a milder phenotype with less pronounced QT prolongation and a lower percentage of syncopal episodes and sudden deaths (PMID: 9386136); Observed in the homozygous state in one individual with LQTS and hearing loss (PMID: 28438721); Published functional studies demonstrate decreased binding affinity for its co-factor, PIP2, causing impaired potassium channel function (PMID: 9312006, 15746441, 19934648, 21576493, 22456477, 24681627, 25037568); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 3126); This variant is associated with the following publications: (PMID: 14760488, 15746441, 9312006, 12522251, 19261104, 15140888, 12877697, 15234419, 15840476, 19934648, 25037568, 16540748, 14998624, 19862833, 21576493, 26669661, 24363352, 26907222, 27761162, 18174212, 22456477, 29037160, 10090886, 28449774, 32383558, 34505893, 9386136, 24681627, 19716085, 28438721) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 13, 2022	- -

Long QT syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 28, 2019	Variant summary: KCNQ1 c.1663C>T (p.Arg555Cys) results in a non-conservative amino acid change located in the C-terminal domain (IPR013821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.1e-05 in 179696 control chromosomes (gnomAD). c.1663C>T has been reported in the literature in several heterozygous individuals affected with Long QT Syndrome (e.g. Donger 1997, Imboden 2006, Yasuda 2008, Al-Hassnan 2017), where the variant was also observed to segregate with the disease in several families, although with a reduced penetrance (Donger 1997). In these families the affected individuals had a milder phenotype with later age of onset, and often normal- or borderline QTc intervals, however authors described several cases with drug-induced symptoms (Donger 1997). In a consanguineous family the variant was described in homozygosity, where the patient had an early age of onset (3 yo), experienced syncope and deafness, and had a clearly prolonged QTc on the ECG (Al-Hassnan 2017). Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated compromised potassium channel function as measured by decreased "slow delayed rectifier potassium current" with an impaired PIP2 regulation (e.g. Matavel 2010, Barsheshet 2012) consistent with the established pathophysiology of LQT1. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 555 of the KCNQ1 protein (p.Arg555Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with long QT syndrome (PMID: 9386136, 14998624, 19716085, 23631430). ClinVar contains an entry for this variant (Variation ID: 3126). 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: 15746441, 19841300, 19934648, 21576493, 22456477, 24681627, 25037568, 25348405). For these reasons, this variant has been classified as Pathogenic. -

Prolonged QT interval Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Jan 31, 2017

The KCNQ1 Arg555Cys variant has been reported in multiple patients with Long QT syndrome (Kapplinger JD, et al., 2010; Tester DJ, et al., 2005; Paulussen AD, et al., 2005; Nemec J, et al., 2003; Donger C, et al., 1997) and has been shown to segregate with disease in 3 large families (Donger C, et al., 1997). We identified this variant in 1 proband with Long QT syndrome. The variant is present at low frequency in the Exome Aggregation Consortium dataset (MAF=0.000036; http://exac.broadinstitute.org/). Computational tools SIFT, PolyPhen2 and MutationTaster predict this variant to be deleterious. Functional work performed on this variant has consistently shown that KCNQ1 Arg555Cys results in reduced affinity of PIP2 which is necessary for channel activity, inhibition of potassium channel activity would result in prolonged QT intervals (Barsheshet A, et al., 2012; Matavel A, et al., 2010; Park KH, et al., 2005). In summary, based on multiple reports of Long QT patients harbouring the variant, segregation data, functional studies in support of a damaging effect and rarity in the general population, we classify KCNQ1 Arg555Cys as "Pathogenic". -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 02, 2024

The c.1663C>T (p.R555C) alteration is located in exon 13 (coding exon 13) of the KCNQ1 gene. This alteration results from a C to T substitution at nucleotide position 1663, causing the arginine (R) at amino acid position 555 to be replaced by a cysteine (C). Based on data from gnomAD, the T allele has an overall frequency of 0.001% (2/179696) total alleles studied. The highest observed frequency was 0.006% (1/16062) of European (Finnish) alleles. This alteration has been reported in numerous individuals with long QT syndrome (LQTS) and has been shown to segregate with disease across multigenerational families, although the QT prolongation is typically mild and many of the reported cardiac events are drug-induced (Donger, 1997). This amino acid position is highly conserved in available vertebrate species. In several functional in vitro analyses, this alteration has adversely affected the voltage-gated potassium ion channel, resulting in decreased current amplitude, prolongation of the channel activation threshold, and accelerated channel deactivation (Chouabe, 1997; Dvir, 2014). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Cardiac arrhythmia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 06, 2018

This missense variant is located in the C-terminal cytoplasmic domain of the KCNQ1 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. Multiple experimental functional studies have shown that this variant causes decreased binding affinity for PIP2 and impairs the potassium channel function (PMID: 15746441, 19934648, 21576493, 22456477, 24681627, 25037568). This variant has been reported in over 10 unrelated individuals affected with long QT syndrome (PMID: 15840476, 19716085, 22456477, 23631430, 26715165). This variant has been reported to segregate with disease in 44 individuals from 3 different families (PMID: 9386136). In this study, this variant was associated with a mild phenotype compared to other pathogenic variants in the same gene. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). In addition, different variants occurring at the same amino acid position (p.Arg555Ser, p.Arg555His) are considered deleterious (Clinvar), suggesting that arginine at this position is important for the channel function. Based on available evidence, this variant is classified as 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:12877697;PMID:14760488;PMID:15840476;PMID:18174212;PMID:19716085;PMID:19934648;PMID:15746441;PMID:22456477). 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	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;.;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	3.1	M;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-7.0	D;.;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0	D;.;D
Polyphen		1.0	D;.;D
Vest4		0.99
MutPred		0.96		Loss of MoRF binding (P = 0.0016);.;.;
MVP		0.98
MPC		1.4
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.90
gMVP		1.0

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: rs120074185; hg19: chr11-2797262; COSMIC: COSV104548712; COSMIC: COSV104548712;