ClinVar Genomic variation as it relates to human health
NM_000238.4(KCNH2):c.1750G>A (p.Gly584Ser)
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_000238.4(KCNH2):c.1750G>A (p.Gly584Ser)
Variation ID: 67261 Accession: VCV000067261.52
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q36.1 7: 150951643 (GRCh38) [ NCBI UCSC ] 7: 150648731 (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 Feb 6, 2015 Oct 20, 2024 Mar 11, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000238.4:c.1750G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000229.1:p.Gly584Ser missense NM_001204798.2:c.730G>A NP_001191727.1:p.Gly244Ser missense NM_001406753.1:c.1462G>A NP_001393682.1:p.Gly488Ser missense NM_001406755.1:c.1573G>A NP_001393684.1:p.Gly525Ser missense NM_001406756.1:c.1462G>A NP_001393685.1:p.Gly488Ser missense NM_001406757.1:c.1450G>A NP_001393686.1:p.Gly484Ser missense NM_172056.3:c.1750G>A NP_742053.1:p.Gly584Ser missense NM_172057.3:c.730G>A NP_742054.1:p.Gly244Ser missense NR_176254.1:n.2158G>A NR_176255.1:n.1031G>A NC_000007.14:g.150951643C>T NC_000007.13:g.150648731C>T NG_008916.1:g.31284G>A LRG_288:g.31284G>A LRG_288t1:c.1750G>A LRG_288p1:p.Gly584Ser LRG_288t2:c.1750G>A LRG_288p2:p.Gly584Ser LRG_288t3:c.730G>A LRG_288p3:p.Gly244Ser Q12809:p.Gly584Ser - Protein change
- G244S, G584S, G488S, G525S, G484S
- Other names
- p.G584S:GGC>AGC
- Canonical SPDI
- NC_000007.14:150951642:C:T
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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.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
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
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. |
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KCNH2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3219 | 3305 |
Conditions - Germline
Condition
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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
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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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Likely pathogenic (2) |
criteria provided, single submitter
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Jan 29, 2019 | RCV000057974.15 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Mar 11, 2024 | RCV000157264.16 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jun 30, 2022 | RCV000181816.35 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 22, 2023 | RCV000470290.16 | |
Pathogenic (1) |
no assertion criteria provided
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Feb 10, 2016 | RCV000477917.10 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 14, 2023 | RCV000618627.13 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jul 14, 2019 | RCV001841704.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 11, 2024 | RCV004562234.1 |
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. |
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Pathogenic
(Jun 30, 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: SCV000234119.11
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
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; … (more)
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 using patch clamp assays in transfected Chinese hamster ovary (CHO) cells and Xenopus oocytes suggest that the G584S mutant channel causes a loss of the rapid delayed rectifier current due to trafficking and gating defects (Zhao et al., 2009; Perry et al., 2016); Reported as a pathogenic/likely pathogenic variant in ClinVar (ClinVar Variant ID#67261; ClinVar); This variant is associated with the following publications: (PMID: 21440677, 27807201, 24606995, 22581653, 31447099, 15176425, 20659946, 20566482, 22949429, 25417810, 25649125, 26187847, 26669661, 19490267, 26958806, 19716085, 10862094, 23098067, 15840476, 10973849, 10483966, 19841300, 31358886, 28431243, 32048431, 34319147, 33087929) (less)
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Likely pathogenic
(Sep 14, 2023)
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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: SCV000738197.6
First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024 |
Comment:
The p.G584S variant (also known as c.1750G>A), located in coding exon 7 of the KCNH2 gene, results from a G to A substitution at nucleotide … (more)
The p.G584S variant (also known as c.1750G>A), located in coding exon 7 of the KCNH2 gene, results from a G to A substitution at nucleotide position 1750. The glycine at codon 584 is replaced by serine, an amino acid with similar properties, and is located in the S5/pore transmembrane spanning region. This alteration has been detected in long QT syndrome (LQTS) cohorts, a sudden cardiac arrest/death cohort, and cohorts referred for LQTS genetic testing with varying levels of clinical detail (Splawski I et al. Circulation. 2000;102:1178-85; Kapa S et al. Circulation. 2009;120:1752-60; Kapplinger JD et al. Heart Rhythm. 2009;6:1297-303; Stattin EL et al. BMC Cardiovasc Disord. 2012;12:95; Christiansen M et al. BMC Med Genet. 2014;15:31; Li MH et al. Hum Genomics. 2015;9:15; Nakajima T et al. Circ J. 2015;79(6):1185-92). This alteration has been reported to segregate with disease in a family with symptomatic individuals and members with moderate QTc prolongation where, overall, carriers had longer QT intervals than non-carriers; however, some individuals with QT prolongation were not indicated as carriers of this alteration, suggesting that this alteration is associated with reduced phenotypic penetrance (Kerr SM et al. Sci Rep, 2019 Jul;9:10964; Swan H et al. J Am. Coll Cardiol. 1999;34:823-9; Laitinen P et al. Hum Mutat. 2000;15:580-1). In vitro functional studies have suggested this alteration may have some impact on channel function or protein trafficking (Zhao JT et al. J Cardiovasc Electrophysiol. 2009;20:923-30; Perry MD et al. J Physiol Lond. 2016;594:4031-49). Internal analysis indicates this alteration may be structurally disruptive (Wang W et al. Cell. 2017;169(3):422-430.e10). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Pathogenic
(Mar 11, 2024)
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criteria provided, single submitter
Method: clinical testing
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Short QT syndrome type 1
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV005049835.1
First in ClinVar: Jun 09, 2024 Last updated: Jun 09, 2024 |
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Pathogenic
(Mar 11, 2024)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome 2
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV005049912.1
First in ClinVar: Jun 09, 2024 Last updated: Jun 09, 2024 |
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Pathogenic
(Jun 01, 2021)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001746020.20
First in ClinVar: Jul 10, 2021 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 2
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Likely pathogenic
(Jan 29, 2019)
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criteria provided, single submitter
Method: clinical testing
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Congenital long QT syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000731739.2
First in ClinVar: Oct 09, 2016 Last updated: Jul 03, 2020 |
Comment:
The p.Gly584Ser variant in KCNH2 has been reported in 4 individuals with long QT syndrome, segregated with disease in at least 11 affected relatives from … (more)
The p.Gly584Ser variant in KCNH2 has been reported in 4 individuals with long QT syndrome, segregated with disease in at least 11 affected relatives from 2 families (Swan 1999, Laitinen 2000, Zhao 2009, Giudicessi 2012, and Li 2015), and has also been reported by other clinical laboratories in ClinVar (Variation ID: 67261). In vitro functional studies provide some evidence that the p.Gly584Ser variant may impact protein function (Zhao 2009). This variant was absent from large population studies. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, the p.Gly584Ser variant is likely pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(Aug 17, 2019)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001715980.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Comment:
PS3_Supporting, PS-Moderate, PP2, PP3, PP1_Moderate, PM1
Number of individuals with the variant: 1
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome 2
Affected status: yes
Allele origin:
germline
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Genomics England Pilot Project, Genomics England
Accession: SCV001760195.1
First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021 |
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Likely pathogenic
(Jul 14, 2019)
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criteria provided, single submitter
Method: clinical testing
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Cardiac arrhythmia
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV001350154.2
First in ClinVar: Jun 22, 2020 Last updated: Jan 12, 2022 |
Comment:
This missense variant replaces glycine with serine at codon 584 in the extracellular linker region between transmembrane domain S5 and pore-forming region of the KCNH2 … (more)
This missense variant replaces glycine with serine at codon 584 in the extracellular linker region between transmembrane domain S5 and pore-forming region of the KCNH2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. Experimental functional studies have shown that the mutant protein carrying this variant traffics to the cell membrane normally but has moderate impact on the channel function (PMID: 19490267, 26958806). This variant has been reported to segregate with long QT syndrome in a large multigenerational family (PMID: 19490267). This variant has also been reported in multiple unrelated individuals affected with long QT syndrome (PMID: 10862094, 10973849, 22949429, 23098067, 24606995, 25925977). This variant has been identified in 2/251412 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic. (less)
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Pathogenic
(Jun 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome 2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
paternal
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV004045970.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Acute kidney injury (present) , Renovascular hypertension (present) , Stage 5 chronic kidney disease (present)
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Pathogenic
(Aug 22, 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: SCV000543426.8
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. … (more)
An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 584 of the KCNH2 protein (p.Gly584Ser). This variant is present in population databases (rs199473428, gnomAD 0.002%). This missense change has been observed in individuals with long QT syndrome (LQTS) (PMID: 10862094, 10973849, 19490267, 22949429, 24606995). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 67261). Experimental studies have shown that this missense change affects KCNH2 function (PMID: 19490267). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Feb 10, 2016)
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no assertion criteria provided
Method: research
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Long QT syndrome 2
Short QT syndrome type 1
Affected status: yes
Allele origin:
maternal
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Division of Human Genetics, Children's Hospital of Philadelphia
Study: CSER-PediSeq
Accession: SCV000536779.1 First in ClinVar: Apr 23, 2017 Last updated: Apr 23, 2017 |
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Pathogenic
(Sep 29, 2014)
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no assertion criteria provided
Method: clinical testing
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Long QT syndrome 2
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV000206994.1
First in ClinVar: Feb 06, 2015 Last updated: Feb 06, 2015 |
Number of individuals with the variant: 2
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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: SCV000089494.3
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:10483966;PMID:10862094;PMID:10973849;PMID:15840476;PMID:19490267;PMID:19716085;PMID:19841300). 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:10483966;PMID:10862094;PMID:10973849;PMID:15840476;PMID:19490267;PMID:19716085;PMID:19841300). 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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An actionable KCNH2 Long QT Syndrome variant detected by sequence and haplotype analysis in a population research cohort. | Kerr SM | Scientific reports | 2019 | PMID: 31358886 |
Cryo-EM Structure of the Open Human Ether-à-go-go-Related K(+) Channel hERG. | Wang W | Cell | 2017 | PMID: 28431243 |
Rescue of protein expression defects may not be enough to abolish the pro-arrhythmic phenotype of long QT type 2 mutations. | Perry MD | The Journal of physiology | 2016 | PMID: 26958806 |
Utility and limitations of exome sequencing as a genetic diagnostic tool for conditions associated with pediatric sudden cardiac arrest/sudden cardiac death. | Li MH | Human genomics | 2015 | PMID: 26187847 |
Follow-up of 316 molecularly defined pediatric long-QT syndrome patients: clinical course, treatments, and side effects. | Koponen M | Circulation. Arrhythmia and electrophysiology | 2015 | PMID: 26063740 |
Unveiling specific triggers and precipitating factors for fatal cardiac events in inherited arrhythmia syndromes. | Nakajima T | Circulation journal : official journal of the Japanese Circulation Society | 2015 | PMID: 25925977 |
Mutations in Danish patients with long QT syndrome and the identification of a large founder family with p.F29L in KCNH2. | Christiansen M | BMC medical genetics | 2014 | PMID: 24606995 |
Founder mutations characterise the mutation panorama in 200 Swedish index cases referred for Long QT syndrome genetic testing. | Stattin EL | BMC cardiovascular disorders | 2012 | PMID: 23098067 |
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 |
Cloninger's temperament traits and inherited long QT syndrome. | Määttänen I | Journal of psychosomatic research | 2011 | PMID: 21911102 |
A history of stressful life events, prolonged mental stress and arrhythmic events in inherited long QT syndrome. | Hintsa T | Heart (British Cardiac Society) | 2010 | PMID: 20659946 |
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 |
Not all hERG pore domain mutations have a severe phenotype: G584S has an inactivation gating defect with mild phenotype compared to G572S, which has a dominant negative trafficking defect and a severe phenotype. | Zhao JT | Journal of cardiovascular electrophysiology | 2009 | PMID: 19490267 |
Postmortem long QT syndrome genetic testing for sudden unexplained death in the young. | Tester DJ | Journal of the American College of Cardiology | 2007 | PMID: 17222736 |
Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing. | Tester DJ | Heart rhythm | 2005 | PMID: 15840476 |
Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. | Splawski I | Circulation | 2000 | PMID: 10973849 |
Survey of the coding region of the HERG gene in long QT syndrome reveals six novel mutations and an amino acid polymorphism with possible phenotypic effects. | Laitinen P | Human mutation | 2000 | PMID: 10862094 |
Sinus node function and ventricular repolarization during exercise stress test in long QT syndrome patients with KvLQT1 and HERG potassium channel defects. | Swan H | Journal of the American College of Cardiology | 1999 | PMID: 10483966 |
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Text-mined citations for rs199473428 ...
HelpRecord 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.