rs199472719

chr11-2572104-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.775C>T(p.Arg259Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,226 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R259H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11 O:1
• Conservation: PhyloP100: 1.65

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 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 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 chr11-2572105-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 11-2572104-C-T is Pathogenic according to our data. Variant chr11-2572104-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2572104-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.775C>T	p.Arg259Cys	missense_variant	5/16	ENST00000155840.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.775C>T	p.Arg259Cys	missense_variant	5/16	1	NM_000218.3	P1
KCNQ1	ENST00000335475.6	c.394C>T	p.Arg132Cys	missense_variant	5/16	1
KCNQ1	ENST00000496887.7	c.514C>T	p.Arg172Cys	missense_variant	6/16	5
KCNQ1	ENST00000646564.2	c.478-11331C>T		intron_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000408 AC: 1 AN: 245266 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 133660

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000549

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459226 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725958

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome 1 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Dec 06, 2023	PS3, PS4_Moderate, PM1, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	Jan 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes	Aug 01, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	Jun 18, 2018	- -

not provided Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 27, 2023	Not observed at a significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as mammalian cells transfected with R259C resulted in functional channels with a significantly smaller current compared to wild-type channels (Kubota et al., 2000); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22949429, 28992529, 27868350, 29439887, 34505893, 31518351, 25525159, 25559286, 11021476, 12402336, 16922724, 23124029, 17470695, 19716085, 21350584, 28749187, 19841300, 23995044, 24190995, 12566525, 15840476, 15234419, 23158531, 22581653, 30591322, 31737537) -
Likely pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Dec 02, 2014	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNQ1 p.Arg259Cys Based on the strong case data and the absence in general population samples, we consider this variant likely disease causing. This variant has been reported in at least 9 unrelated cases. There is no segregation data available. Kubota T et al (2000) first reported the variant in a 47 year old female with hypokalemia-induced long QT. She presented with Torsades de Pointes, QTc of 620msec and recurrent syncopal episodes. Three of her relatives were genotyped and all were negative for the variant (their QTC was 430ms, 380ms and 440ms). This is likely the same case later included in a genotype-phenotype study by the same group (Shimizu et al 2004). Jongbloed et al (2002) reported the variant in 1 out of 32 patients with long QT syndrome from Belgium and Holland. The same group reported this variant in another paper the following year on genotype-phenotype correlations (Van Langen et al 2003). Given the described recruitment these are likely the same patient. Tester et al (2005) also reported the variant in 1 out of 541 unrelated cases referred for long QT genetic testing at a research lab lead by Dr. Mike Ackerman. Individual phenotype was not reported, however the average QTc of the study population was 482 ms and 29% of the total cohort had a Schwarts score > 4. Millat et al (2006) observed p.Arg259Cys in a 9 year old female of either Spanish or French ancestry who presented with syncope triggered by exercise, her QTc was not measured. The variant was reported in 5 individuals in the Familion compendium, which includes 2500 patients referred for clinical long QT genetic testing (Kapplinger et al 2009). Of note in considering the cases reported by Kapplinger et al (2009) is the lack of phenotypic data on this cohort, the low yield of 36% (vs. 70% in cohorts with firm diagnoses of long QT), and the lack of clarity regarding which variants were seen with another variant (9% of the cohort had multiple variants). Kapa et al (2009) report p.Arg259Cys in 1 out of 388 unrelated “definite” (Schwarts score >4 and/or QTc >480ms) cases., however that case may overlap with Kapplinger et al (2009) and Tester et al (2005) as the sample came from the Mayo, Familion, and Dutch cohorts. Cueno et al (2013) reported two patients with this variant in a cohort of long QT cases presenting with fetal arrhythmia. Dr. Ackerman is a co-author on that paper, however the cases were recruited from centers in Chicago, Japan, and Salt Lake City so they likely do not overlap with Ackerman’s cohort (recruitment described in Mitchell et al 2012). However, the genetic analysis was done either at GeneDx or Familion, so these two cases may overlap with those published by Kapplinger et al (2009). Moss et al (2007) include one individual with this variant and long QT in a genotype-phenotype correlation study. That sample was drawn from the international registry, the Dutch registry, and the Japanese registry, so that case may overlap with Kutoba et al, Shimizu et al, Jongbloed et aland Van Langen e al. The variant was also included in a paper by Ackerman’s group on variant classification, which likely overlaps prior reports (Guidicessi et al 2012). This is a non-conservative amino acid change with a polar, hydrophilic Arginine replaced with a nonpolar hydrophobic Cysteine. The variant is located in the cytoplasmic loop (S4-S5) of the transmembrane KCNQ1 channel. PolyPhen predicts the amino acid change to be probably damaging. Additional missense variants at the same (p.Arg259Cys, p,Arg259Lys) and nearby codons (p.Val254Leu, p.Val254Met, p.His258Asn, p. His258Arg, p.His258Pro, p.Glu261Asp, p.Glu261Lys, p.Glu261Gln, p.Leu262Val, p.Thr265Ile) h -

Congenital long QT syndrome Pathogenic:1 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:11021476;PMID:12402336;PMID:12566525;PMID:15840476;PMID:16922724;PMID:19716085;PMID:19841300;PMID:15234419;PMID:17470695). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 16, 2020	The p.Arg259Cys variant in KCNQ1 has been reported in the heterozygous state in at least 10 individuals with Long QT Syndrome (LQTS), including a de novo occurrence where maternity and paternity was not confirmed and 2 individuals with childhood onset LQTS (Kubota 2000, PMID: 11021476; Jongbloed 2002, PMID: 12402336; Van Langen 2003, PMID: 12566525; Shimizu 2004, PMID: 15234419; Moss 2007, PMID:17470695; Kapa 2009, PMID: 19841300; Hofman 2011, PMID: 21350584; Crotti 2012, PMID:23158531, Giudicessi 2012, PMID:22949429, Mitchell 2012, PMID:23124029). Additionally, it has been identified in at least 5 individuals referred for LQTS clinical genetic testing (Tester 2005, PMID: 15840476; Kapplinger 2009, PMID:19716085) and in 1 child with exercise-triggered syncope (Millat 2006, PMID: 16922724). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 53100) and has been identified in 0.005% (1/18224) of East Asian chromosomes in gnomAD (http://gnomad.broadinstitute.org/). In vitro functional studies support an impact on protein function that is consistent with a dominant negative effect (Kubota 2000, PMID: 11021476) and computational prediction tools and conservation analyses are consistent with pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant LQTS. ACMG/AMP Criteria applied: PM2, PP3, PS3_supporting, PS4_Moderate, PM6. -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 17, 2024

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 259 of the KCNQ1 protein (p.Arg259Cys). This variant is present in population databases (rs199472719, gnomAD 0.006%). This missense change has been observed in individuals with long QT syndrome (PMID: 11021476, 12402336, 15234419, 21350584, 22949429, 23124029, 23158531). ClinVar contains an entry for this variant (Variation ID: 53100). 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: 11021476). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2022

The p.R259C pathogenic mutation (also known as c.775C>T), located in coding exon 5 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 775. The arginine at codon 259 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the S4-S5 linking region. This alteration has been previously reported in multiple long QT syndrome (LQTS) cohorts with varying levels of clinical detail, and, in one case, was reported as occurring de novo (Jongbloed R et al. Hum Mutat. 2002;20:382-91; Tester DJ et al. Heart Rhythm. 2005 May;2:507-17; Millat G et al. Clin Genet. 2006;70:214-27; Moss AJ et al. Circulation, 2007 May;115:2481-9; Hofman N et al. Neth Heart J. 2011;19:10-16; Crotti L et al. J Am Coll Cardiol. 2012;60:2515-24). In addition, this alteration was detected in a clinically "definite" LQTS case, and has also been reported in association with hypokalemia-induced LQTS and fetal arrhythmia (Kubota T et al. J Cardiovasc Electrophysiol. 2000;11:1048-54; Kapa S et al. Circulation. 2009;120:1752-60; Cuneo BF et al. Circ Arrhythm Electrophysiol. 2013;6:946-51). Furthermore, other alterations affecting this amino acid (p.R259H, c.776G>A and R259L, c.776G>T) have also been reported in association with LQTS (Millat G et al. Clin Genet. 2006;70:214-27; Kapa S et al. Circulation. 2009;120(18):1752-60). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.50
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-7.9	D;D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.97, 0.95
MutPred		0.93		.;Loss of helix (P = 0.0304);.;
MVP		0.97
MPC		1.4
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.92
gMVP		0.97

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: rs199472719; hg19: chr11-2593334;