rs199472720

chr11-2572105-G-Achr11-2572105-G-Cchr11-2572105-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM5 PP3_Strong PP5

The NM_000218.3(KCNQ1):c.776G>A(p.Arg259His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,610,292 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R259C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10 U:1 O:1
• Conservation: PhyloP100: 9.14

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 Likely_pathogenic. Variant got 9 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
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 11-2572105-G-A is Pathogenic according to our data. Variant chr11-2572105-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53101.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, not_provided=1, Likely_pathogenic=6, Pathogenic=4}. Variant chr11-2572105-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.776G>A	p.Arg259His	missense_variant	5/16	ENST00000155840.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.776G>A	p.Arg259His	missense_variant	5/16	1	NM_000218.3	P1
KCNQ1	ENST00000335475.6	c.395G>A	p.Arg132His	missense_variant	5/16	1
KCNQ1	ENST00000496887.7	c.515G>A	p.Arg172His	missense_variant	6/16	5
KCNQ1	ENST00000646564.2	c.478-11330G>A		intron_variant

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000163 AC: 4 AN: 244876 Hom.: 0 AF XY: 0.0000225 AC XY: 3 AN XY: 133458

Gnomad AFR exome AF: 0.0000645

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: 0.00

Gnomad NFE exome AF: 0.0000272

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000165 AC: 24 AN: 1457986 Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14 AN XY: 725428

Gnomad4 AFR exome AF: 0.0000299

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: 0.0000180

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152306 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74466

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

ExAC AF: 0.00000827 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.0000594

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:10 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Long QT syndrome 1 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	Oct 11, 2021	Incidental finding in clinical exome sequencing. PS1, PS3, PP3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jan 30, 2018	This c.776G>A (p.Arg259His) variant in the KCNQ1 gene has been reported in multiple LQTS/SQTS patients with significantly higher prevalence than that observed as extremely low in general population according to gnomad database. Arginine at amino acid position 259 is highly conserved during evolution. Arg259Cys, Arg259Gly and Arg259Leu have been reported in multiple LQTS/SQTS patients as deleterious mutations [PMID: 11021476, 15840476, 19716085, 27868350, 21350584]. Multiple in silico predictions suggest this arginine to histidine change is deleterious. Based upon above evidences, this c.776G>A (p.Arg259His) variant in the KCNQ1 gene is classified as likely pathogenic. -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Sep 21, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 28, 2023	Reported in a 63-year-old asymptomatic male with a prolonged QTc and family history of sudden cardiac death (Millat et al., 2006) and observed in several individuals referred for LQTS testing at GeneDx; Reported in two unrelated individuals with short QT syndrome and a history of sudden cardiac arrest (Mazzanti et al., 2014; Wu et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest that p.(R259H) may have a gain-of-function effect associated with QT interval shortening (Wu et al., 2015); however, further studies are needed to clarify the functional impact of this variant and its potential role in SQTS or LQTS; 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: 28814790, 29759541, 31315195, 19862833, 25974115, 26370830, 30337886, 29021305, 29241489, 26346102, 31447099, 31589614, 16922724, 24291113) -

Short QT syndrome type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn

Oct 11, 2021

Incidental finding in clinical exome sequencing. PS1, PS3, PP3 -

KCNQ1-Related Disorders Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

DASA

Jan 05, 2022

The c.776G>A;p.(Arg259His) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID 53101; PMID: 16922724; 24291113; 26346102) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 26346102) - PS3_supporting. The variant is located in a mutational hot spot and/or critical and well-established functional domain (S4-S5 domain; PMID: 16922724) - PM1. The variant is present at low allele frequencies population databases (rs199472720 – gnomAD 0.0001314%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. Pathogenic missense variant in this residue have been reported (ClinVar 53102; 53100; PMID: 11021476, 21350584, 23158531) - PM5. In summary, the currently available evidence indicates that the variant is pathogenic. -

Atrial fibrillation, familial, 3;C1865019:Short QT syndrome type 2;C4551647:Long QT syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Jun 08, 2021

PS3, PP3, PM1 -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 24, 2023

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 259 of the KCNQ1 protein (p.Arg259His). This variant is present in population databases (rs199472720, gnomAD 0.004%). This missense change has been observed in individuals with long QT syndrome and short QT syndrome (PMID: 16922724, 24291113, 26346102). ClinVar contains an entry for this variant (Variation ID: 53101). 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: 26346102). This variant disrupts the p.Arg259 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11021476, 21350584, 23158531). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 13, 2022

The p.R259H variant (also known as c.776G>A), located in coding exon 5 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 776. The arginine at codon 259 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in individuals with short QT syndrome (Mazzanti A et al. J Am Coll Cardiol. 2014;63:1300-8; Wu ZJ et al. J Geriatr Cardiol. 2015;12:394-401; Mazzanti A et al. J Am Coll Cardiol. 2017;70(24):3010-3015), in an asymptomatic individual with QTc prolongation and family history of sudden death (Millat G et al. Clin Genet. 2006;70:214-27), and a case with cardiac arrest who was reported to have long QT syndrome (Tiesmeier J et al. Resuscitation. 2021 11;168:176-185). This variant has also been detected in cohorts not selected for the presence of arrhythmia; however, clinical details were limited (Capalbo A et al. PLoS Genet. 2019 10;15(10):e1008409; Zouk H et al. Am J Hum Genet. 2019 09;105(3):588-605). An in vitro assay indicated this variant to impact channel function, resulting in a gain-of-function effect (Wu ZJ et al. J Geriatr Cardiol. 2015;12:394-401). Internal structural analysis indicates this alteration lies in the S4-S5 linking region and may impact modulation of channel gating (Eckey K et al. J Biol Chem. 2014;289(33):22749-58). In addition, other alterations affecting this amino acid (p.R259C (c.775C>T) p.R259L (c.776G>T), and p.R259G (c.775C>G)) have also been reported in association with LQTS (Kapa S et al. Circulation. 2009;120(18):1752-60; Coto E et al. Am J Med Genet A. 2017;173(3):749-752). 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. -

Cardiac arrhythmia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

May 17, 2023

This missense variant replaces arginine with histidine at codon 259 of the KCNQ1 protein. This variant is found within a highly conserved region of the cytoplasmic linker. Rare nontruncating variants in this region (a.a. 249-261) have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). A functional study has shown that this variant alters the channel electrophysiological properties by significantly decreasing current density and peak current (PMID: 34798354), which are inconsistent with the findings from another study (PMID: 26346102). This variant has been reported in several individuals affected with or suspected of having long QT syndrome (PMID: 16922724, 34798354, ClinVar SCV000234416.14), in two individuals affected with short QT syndrome (PMID: 24291113, 26346102), in one individual suspected of having epilepsy (PMID: 31696929), and in an individual with need for cardiopulmonary resuscitation attempts (PMID: 34389451). Different missense substitutions at this codon (p.Arg259Cys, p.Arg259Leu) are known to be pathogenic (ClinVar variation ID 53100, 53102), indicating that arginine at this position is important for KCNQ1 protein function. This variant has been identified in 5/271834 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion for a pathogenic role, the available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

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:16922724). 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	0.91
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.53
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-4.9	D;D;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.91, 0.91
MutPred		0.91		.;Gain of catalytic residue at I257 (P = 0.1169);.;
MVP		0.99
MPC		1.3
ClinPred		0.98	D
GERP RS		4.0
Varity_R		0.85
gMVP		0.94

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: rs199472720; hg19: chr11-2593335; COSMIC: COSV99325916;