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)
ClinVar Genomic variation as it relates to human health
NM_000218.3(KCNQ1):c.691C>T (p.Arg231Cys)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(11)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
11
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000218.3(KCNQ1):c.691C>T (p.Arg231Cys)
Variation ID: 53086 Accession: VCV000053086.38
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11p15.5 11: 2572020 (GRCh38) [ NCBI UCSC ] 11: 2593250 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Sep 9, 2016 Oct 20, 2024 Jul 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000218.3:c.691C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000209.2:p.Arg231Cys missense NM_001406836.1:c.691C>T NP_001393765.1:p.Arg231Cys missense NM_001406837.1:c.421C>T NP_001393766.1:p.Arg141Cys missense NM_181798.2:c.310C>T NP_861463.1:p.Arg104Cys missense NR_040711.2:n.584C>T NC_000011.10:g.2572020C>T NC_000011.9:g.2593250C>T NG_008935.1:g.132030C>T LRG_287:g.132030C>T LRG_287t1:c.691C>T LRG_287p1:p.Arg231Cys LRG_287t2:c.310C>T LRG_287p2:p.Arg104Cys P51787:p.Arg231Cys - Protein change
- R231C, R104C, R141C
- Other names
-
p.R231C:CGC>TGC
- Canonical SPDI
- NC_000011.10:2572019:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| KCNQ1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
1721 | 2664 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| not provided (1) |
no classification provided
|
- | RCV000057733.5 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jul 1, 2024 | RCV000182100.27 | |
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Aug 1, 2023 | RCV000240642.8 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 4, 2024 | RCV001385527.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jun 13, 2024 | RCV002362679.4 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 8, 2023 | RCV003591647.1 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Mar 17, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Long QT syndrome 1
Affected status: yes
Allele origin:
germline
|
Center for Medical Genetics Ghent, University of Ghent
Accession: SCV000299261.1
First in ClinVar: Sep 09, 2016 Last updated: Sep 09, 2016 |
|
|
|
Pathogenic
(Jan 12, 2017)
|
criteria provided, single submitter
Method: research
|
Long QT syndrome 1
Affected status: yes
Allele origin:
unknown
|
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Accession: SCV000583963.1
First in ClinVar: Sep 09, 2016 Last updated: Sep 09, 2016 |
Number of individuals with the variant: 1
Clinical Features:
Global developmental delay (present) , Visual impairment (present) , Generalized hypotonia (present) , Abnormal heart morphology (present) , Prominent forehead (present) , Depressed nasal bridge … (more)
Global developmental delay (present) , Visual impairment (present) , Generalized hypotonia (present) , Abnormal heart morphology (present) , Prominent forehead (present) , Depressed nasal bridge (present) , Flat face (present) , Epicanthus (present) , Narrow palate (present) , Heart murmur (present) (less)
|
|
|
Pathogenic
(Mar 08, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Long QT syndrome 1
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002581349.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS3, PM5, PP1_MOD, PM2_SUP, PP3
|
Number of individuals with the variant: 2
Sex: male
|
|
|
Pathogenic
(Nov 22, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000234403.15
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
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 … (more)
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) (less)
|
|
|
Pathogenic
(Aug 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Long QT syndrome 1
Affected status: yes
Allele origin:
germline
|
Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes
Accession: SCV004024176.1
First in ClinVar: Aug 13, 2023 Last updated: Aug 13, 2023 |
|
|
|
Pathogenic
(Jun 13, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002661487.3
First in ClinVar: Nov 29, 2022 Last updated: Aug 11, 2024 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Jan 04, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Long QT syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001585409.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Aug 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiac arrhythmia
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV004358384.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Oct 02, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Long QT syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004829309.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Comment:
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 … (more)
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. (less)
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Jul 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV002062956.20
First in ClinVar: Jan 29, 2022 Last updated: Oct 20, 2024 |
Comment:
KCNQ1: PP1:Strong, PM1, PM2, PM5, PS4:Moderate, PP3, PS3:Supporting
Number of individuals with the variant: 4
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Congenital long QT syndrome
Affected status: unknown
Allele origin:
germline
|
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust
Accession: SCV000089252.3
First in ClinVar: Oct 22, 2013 Last updated: Oct 09, 2016 |
Comment:
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 … (more)
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. (less)
|
|
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Comment:
Comment:
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.
Comment:
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.
Comment:
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.
Comment:
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.
Comment:
KCNQ1: PP1:Strong, PM1, PM2, PM5, PS4:Moderate, PP3, PS3:Supporting
Comment:
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.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
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)
Comment:
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.
Comment:
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.
Comment:
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.
Comment:
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.
Comment:
KCNQ1: PP1:Strong, PM1, PM2, PM5, PS4:Moderate, PP3, PS3:Supporting
Comment:
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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Sex Differences and Utility of Treadmill Testing in Long-QT Syndrome. | Yee LA | Journal of the American Heart Association | 2022 | PMID: 36102233 |
| Genotype-Specific ECG-Based Risk Stratification Approaches in Patients With Long-QT Syndrome. | Rieder M | Frontiers in cardiovascular medicine | 2022 | PMID: 35911527 |
| Disease-linked supertrafficking of a potassium channel. | Huang H | The Journal of biological chemistry | 2021 | PMID: 33600800 |
| Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls. | Walsh R | Genetics in medicine : official journal of the American College of Medical Genetics | 2021 | PMID: 32893267 |
| Early repolarization is associated with symptoms in patients with type 1 and type 2 long QT syndrome. | Laksman ZW | Heart rhythm | 2014 | PMID: 24861447 |
| A KCNQ1 mutation causes a high penetrance for familial atrial fibrillation. | Bartos DC | Journal of cardiovascular electrophysiology | 2013 | PMID: 23350853 |
| Atrial Fibrillation and Long QT Syndrome Presenting in a 12-Year-Old Girl. | Knoche JW | Case reports in pediatrics | 2012 | PMID: 23193492 |
| Overlapping cardiac phenotype associated with a familial mutation in the voltage sensor of the KCNQ1 channel. | Henrion U | Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology | 2012 | PMID: 22613981 |
| Allosteric gating mechanism underlies the flexible gating of KCNQ1 potassium channels. | Osteen JD | Proceedings of the National Academy of Sciences of the United States of America | 2012 | PMID: 22509038 |
| R231C mutation in KCNQ1 causes long QT syndrome type 1 and familial atrial fibrillation. | Bartos DC | Heart rhythm | 2011 | PMID: 20850564 |
| Latent genetic backgrounds and molecular pathogenesis in drug-induced long-QT syndrome. | Itoh H | Circulation. Arrhythmia and electrophysiology | 2009 | PMID: 19843919 |
| Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test. | Kapplinger JD | Heart rhythm | 2009 | PMID: 19716085 |
| KCNE peptides differently affect voltage sensor equilibrium and equilibration rates in KCNQ1 K+ channels. | Rocheleau JM | The Journal of general physiology | 2008 | PMID: 18079560 |
| KCNE1 and KCNE3 stabilize and/or slow voltage sensing S4 segment of KCNQ1 channel. | Nakajo K | The Journal of general physiology | 2007 | PMID: 17698596 |
| Spectrum of pathogenic mutations and associated polymorphisms in a cohort of 44 unrelated patients with long QT syndrome. | Millat G | Clinical genetics | 2006 | PMID: 16922724 |
| Genetic testing in the long QT syndrome: development and validation of an efficient approach to genotyping in clinical practice. | Napolitano C | JAMA | 2005 | PMID: 16414944 |
| Four potassium channel mutations account for 73% of the genetic spectrum underlying long-QT syndrome (LQTS) and provide evidence for a strong founder effect in Finland. | Fodstad H | Annals of medicine | 2004 | PMID: 15176425 |
| Long QT syndrome in neonates: conduction disorders associated with HERG mutations and sinus bradycardia with KCNQ1 mutations. | Lupoglazoff JM | Journal of the American College of Cardiology | 2004 | PMID: 14998624 |
| [Congenital long QT syndrome in newborns]. | Emeriaud G | Archives de pediatrie : organe officiel de la Societe francaise de pediatrie | 2002 | PMID: 12205790 |
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Text-mined citations for rs199473457 ...
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Record last updated Oct 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.