11-2572020-C-T

Variant names:

• chr11-2572020-C-T
• rs199473457
• NM_000218.3:c.691C>T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 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. 14/25 in silico tools predict a damaging 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. R231S) 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:11 O:1
• Conservation: PhyloP100: 7.38
• Publications: 36 publications found

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]

KCNQ1 Gene-Disease associations (from GenCC):

• long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 1

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Jervell and Lange-Nielsen syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Jervell and Lange-Nielsen syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• atrial fibrillation, familial, 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• short QT syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet
• short QT syndrome type 2

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Jervell and Lange-Nielsen syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 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 chr11-2572020-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 280173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 212 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Gene score misZ: 1.8321 (below the threshold of 3.09). Trascript score misZ: 0.90233 (below the threshold of 3.09). GenCC associations: The gene is linked to short QT syndrome type 2, long QT syndrome 1, Jervell and Lange-Nielsen syndrome 1, long QT syndrome, short QT syndrome, Jervell and Lange-Nielsen syndrome, hypertrophic cardiomyopathy, familial atrial fibrillation, atrial fibrillation, familial, 3.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 53086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.691C>T	p.Arg231Cys	missense_variant	Exon 5 of 16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.691C>T	p.Arg231Cys	missense_variant	Exon 5 of 16	1	NM_000218.3	ENSP00000155840.2

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

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000893 Hom.: 0

Bravo AF: 0.00000378

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:5

Aug 01, 2023

Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 08, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 17, 2016

Center for Medical Genetics Ghent, University of Ghent

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2017

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Mar 15, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). Predicted Consequence/Location: Missense variant Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 33600800). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.97 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 1.00 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000053086 /PMID: 12205790). Different missense changes at the same codon (p.Arg231His, p.Arg231Leu, p.Arg231Ser) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000053087, VCV000280173, VCV000519257 /PMID: 16414944 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:2

Nov 22, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KCNQ1: PP1:Strong, PM1, PM2, PM5, PS4:Moderate, PP3, PS3:Supporting -

Long QT syndrome Pathogenic:2

Oct 02, 2023

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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

Jun 13, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Aug 08, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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
CardioboostArm	Pathogenic	1.0
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;.
PhyloP100		7.4
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
Mutation Taster		=6/94	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs199473457; hg19: chr11-2593250;