rs199472814

Positions:

• chr11-2778015-G-A
• chr11-2778015-G-C
• chr11-2778015-G-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.1772G>A​(p.Arg591His) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,352 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. R591C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 5.86

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 1 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 chr11-2778015-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 200857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 11-2778015-G-A is Pathogenic according to our data. Variant chr11-2778015-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 53017.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2778015-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.1772G>A	p.Arg591His	missense_variant	15/16	ENST00000155840.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1772G>A	p.Arg591His	missense_variant	15/16	1	NM_000218.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461352 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727014

Gnomad4 AFR exome AF: 0.0000299

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

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 03, 2022	Reported in multiple individuals in association with LQTS (Neyroud et al., 1999; Inoue et al., 2003; Shimizu et al., 2004; Grunnet et al., 2005; Tester et al., 2005; Moss et al,. 2007; Yasuda et al., 2008; Kapa et al., 2009; Kapplinger et al., 2009; Andrsova et al., 2012; Medlock et al., 2012; Stattin et al., 2012; Cuneo et al., 2013; Robinson et al., 2015; Itoh et al., 2016); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect as R591H causes a reduction in potassium ion current due to a reduction in the number of functional voltage-gated potassium channels in the cell membrane (Kanki et al., 2004; Grunnet et al., 2005; Xu et al., 2009); Reported in ClinVar as pathogenic (ClinVar Variant ID# 53017; ClinVar); This variant is associated with the following publications: (PMID: 17470695, 15840476, 17329207, 22949429, 19716085, 19261104, 16253915, 12388934, 18174212, 19825999, 24713462, 19693805, 15140888, 26669661, 23995044, 10024302, 19841300, 15234419, 25916402, 23098067, 22727609, 12808265, 22885918, 17329209, 31395126, 32048431, 31737537) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	KCNQ1: PM1:Strong, PM2, PM5, PS4:Moderate, PP1, PS3:Supporting -

Long QT syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 05, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 591 of the KCNQ1 protein (p.Arg591His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (PMID: 10024302, 15234419, 16253915, 19261104, 21482651, 22727609, 22949429). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 53017). 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: 16253915, 20662986). This variant disrupts the p.Arg591 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been observed in individuals with KCNQ1-related conditions (PMID: 22429796, 22949429, 23158531), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	research	Dept of Medical Biology, Uskudar University	Jan 08, 2024	Criteria: PS3_Moderate, PS4_Strong, PM1, PM2, PP3 -

Long QT syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Nov 14, 2017

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 20, 2021

The p.R591H pathogenic mutation (also known as c.1772G>A), located in coding exon 15 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 1772. The arginine at codon 591 is replaced by histidine, an amino acid with highly similar properties. This variant has been detected in multiple individuals with long QT syndrome (LQTS) and has also been reported in affected relatives (Neyroud N et al. Circ Res, 1999 Feb;84:290-7; Tester DJ et al. Heart Rhythm, 2006 Jul;3:815-21; Robinson JA et al. Congenit Heart Dis Apr;10:354-61; Grunnet M et al. Heart Rhythm, 2005 Nov;2:1238-49; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298). Functional studies have demonstrated defective protein trafficking and a significant reduction in potassium channel current (Grunnet M et al. Heart Rhythm, 2005 Nov;2:1238-49; Horr S et al. J Cardiovasc Electrophysiol, 2011 Feb;22:193-200; David JP et al. Traffic, 2013 Apr;14:399-411). 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

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:10024302;PMID:15840476;PMID:16253915;PMID:16818214;PMID:17329209;PMID:19716085;PMID:19841300;PMID:15234419;PMID:17470695;PMID:17329207;PMID:9386136). 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	0.87
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D;.;.;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	3.0	M;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.9	D;.;D;.
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;.;D;.
Sift4G	Uncertain	0.0020	D;.;D;.
Polyphen		1.0	D;.;D;.
Vest4		0.96
MutPred		0.95		Loss of MoRF binding (P = 0.0135);.;.;.;
MVP		0.98
MPC		1.3
ClinPred		1.0	D
GERP RS		3.1
Varity_R		0.78
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: rs199472814; hg19: chr11-2799245; COSMIC: COSV50134278;