11-2572020-C-T

Position:

• chr11-2572020-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.691C>T​(p.Arg231Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,194 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. R231H) has been classified as Pathogenic.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: 7.38

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 transmembrane_region Helical; Voltage-sensor; Name=Segment S4 (size 22) in uniprot entity KCNQ1_HUMAN there are 26 pathogenic changes around while only 0 benign (100%) 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 chr11-2572021-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 11-2572020-C-T is Pathogenic according to our data. Variant chr11-2572020-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2572020-C-T is described in Lovd as [Pathogenic]. Variant chr11-2572020-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.691C>T	p.Arg231Cys	missense_variant	5/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.691C>T	p.Arg231Cys	missense_variant	5/16	1	NM_000218.3	ENSP00000155840.2
KCNQ1	ENST00000335475.6	c.310C>T	p.Arg104Cys	missense_variant	5/16	1		ENSP00000334497.5
KCNQ1	ENST00000496887.7	c.430C>T	p.Arg144Cys	missense_variant	6/16	5		ENSP00000434560.2
KCNQ1	ENST00000646564.2	c.478-11415C>T		intron_variant				ENSP00000495806.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152194 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: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152194 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74350

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: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10 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	Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes	Aug 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Mar 08, 2022	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Jan 12, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Mar 17, 2016	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 22, 2021	Published in vitro functional studies demonstrate this variant alters cell surface expression and potassium current kinetics (Bartos et al., 2011; Henrion et al., 2012; Huang et al., 2021); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; 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: 15176425, 16922724, 28479515, 22509038, 33322401, 23193492, 19843919, 12205790, 19716085, 27761162, 17947213, 27291509, 27807201, 28185290, 28341588, 32048431, 31737537, 32383558, 33600800, 20850564, 30975432, 14998624, 23158531, 22613981) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	KCNQ1: PP1:Strong, PM1, PM2, PM5, PS4:Moderate, PP3, PS3:Supporting -

Long QT syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 02, 2023	This missense variant replaces arginine with cysteine at codon 231 of the KCNQ1 protein. This variant is found within a highly conserved region of the transmembrane domain S4 (a.a. 226-248). Rare nontruncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). Functional studies have shown that this variant causes constitutive channel activation and reduced current density after pulses relative to wildtype (PMID: 19843919, 20850564, 22509038, 33600800). This variant has been reported in over ten unrelated individuals affected with long QT syndrome and five individuals from two families affected with atrial fibrillation (PMID: 14998624, 15176425, 16922724, 19716085, 19843919, 20850564, 23193492, 36102233, 35911527). This variant has been reported to be a de novo occurrence in one of the probands (PMID: 14998624). It has been shown that this variant segregates with disease in multiple individuals from at least three of these families (PMID: 20850564, 23193492). This variant has been identified in 1/31342 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 231 of the KCNQ1 protein (p.Arg231Cys). This variant is present in population databases (rs199473457, gnomAD 0.007%). This missense change has been observed in individuals with KCNQ1-related conditions and long QT syndrome and/or atrial fibrillation (PMID: 12205790, 20850564, 22613981). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 53086). 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: 19843919, 20850564, 22509038, 22613981). This variant disrupts the p.Arg231 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16414944, 23350853, 24861447). 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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 13, 2024

The p.R231C pathogenic mutation (also known as c.691C>T), located in coding exon 5 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 691. The arginine at codon 231 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in numerous individuals with long QT syndrome (LQTS) and/or atrial fibrillation (AF), and it has been shown to segregate with disease (Emeriaud G et al. Arch Pediatr 2002 Aug; 9(8):805-9; Lupoglazoff JM et al. J. Am. Coll. Cardiol. 2004 Mar; 43(5):826-30; Millat G et al. Clin. Genet. 2006 Sep; 70(3):214-27; Bartos DC et al. Heart Rhythm 2011 Jan; 8(1):48-55; Henrion U et al. Cell. Physiol. Biochem. 2012 May; 29(5-6):809-18; Knoche JW et al. Case Rep Pediatr 2012 Nov; 2012:124838). In one neonate, this alteration was described as a de novo alteration with confirmed paternity (Lupoglazoff JM et al. J. Am. Coll. Cardiol. 2004 Mar; 43(5):826-30). Multiple functional studies have also demonstrated that this variant alters KCNQ1 channel function (Rocheleau JM et al. J. Gen. Physiol. 2008 Jan; 131(1):59-68; Itoh H et al. Circ Arrhythm Electrophysiol 2009 Oct; 2(5):511-23; Osteen JD et al. Proc. Natl. Acad. Sci. U.S.A. 2012 May; 109(18):7103-8; Bartos DC et al. Heart Rhythm 2011 Jan; 8(1):48-55; Henrion U et al. Cell. Physiol. Biochem. 2012 May; 29(5-6):809-18). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Cardiac arrhythmia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Aug 08, 2023

This missense variant replaces arginine with cysteine at codon 231 of the KCNQ1 protein. This variant is found within a highly conserved region of the transmembrane domain S4 (a.a. 226-248). Rare nontruncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). Functional studies have shown that this variant causes constitutive channel activation and reduced current density after pulses relative to wildtype (PMID: 19843919, 20850564, 22509038, 33600800). This variant has been reported in over ten unrelated individuals affected with long QT syndrome and five individuals from two families affected with atrial fibrillation (PMID: 14998624, 15176425, 16922724, 19716085, 19843919, 20850564, 23193492, 36102233, 35911527). This variant has been reported to be a de novo occurrence in one of the probands (PMID: 14998624). It has been shown that this variant segregates with disease in multiple individuals from at least three of these families (PMID: 20850564, 23193492). This variant has been identified in 1/31342 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the 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:12205790;PMID:14998624;PMID:15176425;PMID:16922724;PMID:19716085;PMID:19843919;PMID:20850564;PMID:22613981). 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	0.97
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	.;D;.
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	4.1	.;H;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-7.8	D;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.98, 0.97
MutPred		0.95		.;Loss of MoRF binding (P = 0.0074);.;
MVP		0.97
MPC		1.4
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.97
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.29		Position offset: 12

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199473457; hg19: chr11-2593250;