ClinVar Genomic variation as it relates to human health
NM_000218.3(KCNQ1):c.502G>C (p.Gly168Arg)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000218.3(KCNQ1):c.502G>C (p.Gly168Arg)
Variation ID: 53053 Accession: VCV000053053.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.5 11: 2570652 (GRCh38) [ NCBI UCSC ] 11: 2591882 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Oct 9, 2016 Aug 25, 2024 Dec 2, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000218.3:c.502G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000209.2:p.Gly168Arg missense NM_001406836.1:c.502G>C NP_001393765.1:p.Gly168Arg missense NM_001406837.1:c.232G>C NP_001393766.1:p.Gly78Arg missense NM_181798.2:c.121G>C NP_861463.1:p.Gly41Arg missense NR_040711.2:n.395G>C NC_000011.10:g.2570652G>C NC_000011.9:g.2591882G>C NG_008935.1:g.130662G>C LRG_287:g.130662G>C LRG_287t1:c.502G>C LRG_287p1:p.Gly168Arg LRG_287t2:c.121G>C LRG_287p2:p.Gly41Arg P51787:p.Gly168Arg - Protein change
- G168R, G41R, G78R
- Other names
- p.G168R:GGG>CGG
- Canonical SPDI
- NC_000011.10:2570651:G:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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KCNQ1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
1720 | 2663 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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not provided (1) |
no classification provided
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- | RCV000057685.4 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 1, 2023 | RCV000182077.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 8, 2022 | RCV000618982.4 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Dec 2, 2023 | RCV000627154.11 |
Submissions - Germline
Classification
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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
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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
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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
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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. |
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Pathogenic
(Jan 07, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000234380.13
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
Observed in multiple unrelated individuals with LQTS referred for genetic testing at GeneDx and in published literature (Donger et al., 1997; Kapplinger et al., 2009); … (more)
Observed in multiple unrelated individuals with LQTS referred for genetic testing at GeneDx and in published literature (Donger et al., 1997; Kapplinger et al., 2009); Not observed at significant frequency 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 that p.(G168R) (nucleotide change not specified) results in lost or reduced channel function (Westenskow et al., 2004; Jons et al., 2011); This variant is associated with the following publications: (PMID: 19716085, 26681611, 28749187, 17091796, 20186784, 27041150, 24103226, 12566525, 14678125, 19490272, 23995044, 21185501, 26318259, 25479336, 9693036, 14531214, 27485560, 10973849, 22949429, 17470695, 22456477, 21451124, 27921062, 33256261, 15051636, 9386136) (less)
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Pathogenic
(Dec 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005198540.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
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Pathogenic
(Jun 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Congenital long QT syndrome
Affected status: yes
Allele origin:
germline
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Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000747996.1
First in ClinVar: May 21, 2018 Last updated: May 21, 2018 |
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Pathogenic
(Dec 02, 2023)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001590790.4
First in ClinVar: May 10, 2021 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 168 of the KCNQ1 protein (p.Gly168Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 168 of the KCNQ1 protein (p.Gly168Arg). This variant is present in population databases (rs179489, gnomAD 0.0009%). This missense change has been observed in individuals with long QT syndrome (PMID: 9386136, 9693036, 10973849, 17905336, 19841300; Invitae). ClinVar contains an entry for this variant (Variation ID: 53053). 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: 15051636, 22456477). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004827271.1
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)
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Comment:
The c.502G>C (p.Gly168Arg) variant in the KCNQ1 gene has been identified in multiple individuals affected with Long QT syndrome (LQTS) (PMID:9386136, 36102233, 33256261, 27921062, 26743238, … (more)
The c.502G>C (p.Gly168Arg) variant in the KCNQ1 gene has been identified in multiple individuals affected with Long QT syndrome (LQTS) (PMID:9386136, 36102233, 33256261, 27921062, 26743238, 24103226, 23995044). This variant, and another variant resulting in the same amino acid substitution c.502G>A (p.Gly168Arg), has been observed in multiple individuals referred for the long QT syndrome genetic testing (PMID: 19716085), and reported to segregate with disease in three families with more than ten affected individuals (PMID: 9693036). The other variant resulting in the same amino acid substitution, c.502G>A (p.Gly168Arg), is a well-known disease-causing variant reported in multiple individuals (>15) with LQTS (PMID: 9693036, 20186784, 10973849, 29952348, 12402336, 17905336, 27485560, 19841300, 22949429). In vitro functional studies on HEK293 cells and X. laevis oocytes have demonstrated that this missense substitution p.Gly168Arg affects KCNQ1 channel function and cause reduced channel current (PMID: 22456477, 15051636). In-silico computational prediction tools suggest that the p.Gly168Arg variant may have deleterious effect on the protein function (REVEL score: 0.937). This variant is found to be rare (1/249646; 0.000004) in the general population database (gnomAD) and interpreted as pathogenic by several submitters in the ClinVar database (ClinVar ID: 53053). Therefore, the c.502G>C (p.Gly168Arg) variant in the KCNQ1 gene is classified as pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(Aug 08, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000737802.5
First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024 |
Comment:
The p.G168R pathogenic mutation (also known as c.502G>C), located in coding exon 3 of the KCNQ1 gene, results from a G to C substitution at … (more)
The p.G168R pathogenic mutation (also known as c.502G>C), located in coding exon 3 of the KCNQ1 gene, results from a G to C substitution at nucleotide position 502. The glycine at codon 168 is replaced by arginine, an amino acid with dissimilar properties. This alteration, and another nucleotide substitution resulting in the same amino acid change (c.502G>A), has been detected in multiple unrelated heterozygous individuals reported to have long QT syndrome (LQTS), has been reported to segregate with LQTS in multiple families, and has been reported in the homozygous state in association with Jervell and Lange-Nielsen syndrome (Donger C et al. Circulation. 1997;96(9):2778-81; Splawski I et al. Genomics. 1998;51(1):86-97; Splawski I et al. Circulation. 2000;102(10):1178-85; Márquez MF et al. Arch Cardiol Mex. 2006;76(3):257-62; Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303; Summers KM et al. Am J Med Genet. 2010;152A(3):613-21; Vyas B. Am. J Med Genet A. 2016;170(6):1510-9; Yoshinaga M et al. Circ J. 2018;82(8):2152-2159). In addition, this alteration has been reported to result in loss of ion channel function in vitro (Westenskow P et al. Circulation. 2004;109(15):1834-41). 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. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Congenital long QT syndrome
Affected status: unknown
Allele origin:
germline
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Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust
Accession: SCV000089204.3
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:9386136;PMID:19716085;PMID:9693036;PMID:12402336;PMID:14531214;PMID:12566525;PMID:17091796;PMID:17470695;PMID:15051636). 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:9386136;PMID:19716085;PMID:9693036;PMID:12402336;PMID:14531214;PMID:12566525;PMID:17091796;PMID:17470695;PMID:15051636). 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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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Sex Differences and Utility of Treadmill Testing in Long-QT Syndrome. | Yee LA | Journal of the American Heart Association | 2022 | PMID: 36102233 |
Clinical Implications and Gender Differences of KCNQ1 p.Gly168Arg Pathogenic Variant in Long QT Syndrome. | Lorca R | Journal of clinical medicine | 2020 | PMID: 33256261 |
Autonomic Function and QT Interval During Night-Time Sleep in Infant Long QT Syndrome. | Yoshinaga M | Circulation journal : official journal of the Japanese Circulation Society | 2018 | PMID: 29952348 |
Differential methylation of lncRNA KCNQ1OT1 promoter polymorphism was associated with symptomatic cardiac long QT. | Coto E | Epigenomics | 2017 | PMID: 28749187 |
Long QT Syndrome and Duodenal Ampullary Adenoma: A New Association. | Asad-Ur-Rahman FN | ACG case reports journal | 2016 | PMID: 27921062 |
Phenotype guided characterization and molecular analysis of Indian patients with long QT syndromes. | Vyas B | Indian pacing and electrophysiology journal | 2016 | PMID: 27485560 |
KCNQ1 mutations associated with Jervell and Lange-Nielsen syndrome and autosomal recessive Romano-Ward syndrome in India-expanding the spectrum of long QT syndrome type 1. | Vyas B | American journal of medical genetics. Part A | 2016 | PMID: 27041150 |
Patient Outcomes From a Specialized Inherited Arrhythmia Clinic. | Adler A | Circulation. Arrhythmia and electrophysiology | 2016 | PMID: 26743238 |
Prevalence and spectrum of electroencephalogram-identified epileptiform activity among patients with long QT syndrome. | Anderson JH | Heart rhythm | 2014 | PMID: 24103226 |
Arrhythmia phenotype during fetal life suggests long-QT syndrome genotype: risk stratification of perinatal long-QT syndrome. | Cuneo BF | Circulation. Arrhythmia and electrophysiology | 2013 | PMID: 23995044 |
Phylogenetic and physicochemical analyses enhance the classification of rare nonsynonymous single nucleotide variants in type 1 and 2 long-QT syndrome. | Giudicessi JR | Circulation. Cardiovascular genetics | 2012 | PMID: 22949429 |
Mutations in cytoplasmic loops of the KCNQ1 channel and the risk of life-threatening events: implications for mutation-specific response to β-blocker therapy in type 1 long-QT syndrome. | Barsheshet A | Circulation | 2012 | PMID: 22456477 |
Mutations at KCNQ1 and an unknown locus cause long QT syndrome in a large Australian family: implications for genetic testing. | Summers KM | American journal of medical genetics. Part A | 2010 | PMID: 20186784 |
Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants. | Kapa S | Circulation | 2009 | PMID: 19841300 |
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 |
Mutations in conserved amino acids in the KCNQ1 channel and risk of cardiac events in type-1 long-QT syndrome. | Jons C | Journal of cardiovascular electrophysiology | 2009 | PMID: 19490272 |
Long QT and Brugada syndrome gene mutations in New Zealand. | Chung SK | Heart rhythm | 2007 | PMID: 17905336 |
Clinical aspects of type-1 long-QT syndrome by location, coding type, and biophysical function of mutations involving the KCNQ1 gene. | Moss AJ | Circulation | 2007 | PMID: 17470695 |
[KCNQ 1 (KvLQT1) missense mutation causing congenital long QT syndrome (Jervell-Lange-Nielsen) in a Mexican family]. | Márquez MF | Archivos de cardiologia de Mexico | 2006 | PMID: 17091796 |
Compound mutations: a common cause of severe long-QT syndrome. | Westenskow P | Circulation | 2004 | PMID: 15051636 |
A candidate locus approach identifies a long QT syndrome gene mutation. | Beery TA | Biological research for nursing | 2003 | PMID: 14531214 |
The use of genotype-phenotype correlations in mutation analysis for the long QT syndrome. | Van Langen IM | Journal of medical genetics | 2003 | PMID: 12566525 |
DHPLC analysis of potassium ion channel genes in congenital long QT syndrome. | Jongbloed R | Human mutation | 2002 | PMID: 12402336 |
Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. | Splawski I | Circulation | 2000 | PMID: 10973849 |
Genomic structure of three long QT syndrome genes: KVLQT1, HERG, and KCNE1. | Splawski I | Genomics | 1998 | PMID: 9693036 |
KVLQT1 C-terminal missense mutation causes a forme fruste long-QT syndrome. | Donger C | Circulation | 1997 | PMID: 9386136 |
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Text-mined citations for rs179489 ...
HelpRecord last updated Sep 29, 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.