ClinVar Genomic variation as it relates to human health
NM_000238.4(KCNH2):c.1744C>T (p.Arg582Cys)
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.1744C>T (p.Arg582Cys)
Variation ID: 14428 Accession: VCV000014428.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q36.1 7: 150951649 (GRCh38) [ NCBI UCSC ] 7: 150648737 (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 Apr 6, 2014 May 1, 2024 Jan 22, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000238.4:c.1744C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000229.1:p.Arg582Cys missense NM_001204798.2:c.724C>T NP_001191727.1:p.Arg242Cys missense NM_001406753.1:c.1456C>T NP_001393682.1:p.Arg486Cys missense NM_001406755.1:c.1567C>T NP_001393684.1:p.Arg523Cys missense NM_001406756.1:c.1456C>T NP_001393685.1:p.Arg486Cys missense NM_001406757.1:c.1444C>T NP_001393686.1:p.Arg482Cys missense NM_172056.3:c.1744C>T NP_742053.1:p.Arg582Cys missense NM_172057.3:c.724C>T NP_742054.1:p.Arg242Cys missense NR_176254.1:n.2152C>T NR_176255.1:n.1025C>T NC_000007.14:g.150951649G>A NC_000007.13:g.150648737G>A NG_008916.1:g.31278C>T LRG_288:g.31278C>T LRG_288t1:c.1744C>T LRG_288p1:p.Arg582Cys LRG_288t2:c.1744C>T LRG_288p2:p.Arg582Cys LRG_288t3:c.724C>T LRG_288p3:p.Arg242Cys Q12809:p.Arg582Cys - Protein change
- R582C, R242C, R523C, R486C, R482C
- Other names
- p.R582C:CGC>TGC
- Canonical SPDI
- NC_000007.14:150951648:G:A
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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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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
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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
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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Pathogenic (1) |
no assertion criteria provided
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Jan 1, 1999 | RCV000015509.27 | |
Likely pathogenic (2) |
criteria provided, single submitter
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Nov 30, 2022 | RCV000057970.5 | |
Pathogenic (3) |
criteria provided, single submitter
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Nov 10, 2020 | RCV000181815.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 27, 2023 | RCV000537059.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 22, 2024 | RCV002399326.3 |
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
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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
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
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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
(Nov 10, 2020)
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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: SCV000234118.8
First in ClinVar: Jul 05, 2015 Last updated: May 29, 2016 |
Comment:
Reported as a potential founder mutation from the Netherlands (Hofman et al., 2011); Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 14428; Landrum … (more)
Reported as a potential founder mutation from the Netherlands (Hofman et al., 2011); Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 14428; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect as this variant results in impaired protein trafficking and channel inactivation (Fougere et al., 2011); This variant is associated with the following publications: (PMID: 10220144, 21376840, 15840476, 19716085, 21350584, 17088455, 9973011, 19038855, 12566525, 18441445, 17293393, 22949429, 32686758) (less)
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Pathogenic
(Nov 27, 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: SCV000627434.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 582 of the KCNH2 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 582 of the KCNH2 protein (p.Arg582Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with LQTS plus a seizure phenotype and Long QT syndrome (LQTS) (PMID: 10220144, 12566525, 18441445, 19038855, 21350584, 22949429). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14428). 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. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 21376840). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 22, 2024)
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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: SCV002712138.3
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.1744C>T (p.R582C) alteration is located in exon 7 (coding exon 7) of the KCNH2 gene. This alteration results from a C to T substitution … (more)
The c.1744C>T (p.R582C) alteration is located in exon 7 (coding exon 7) of the KCNH2 gene. This alteration results from a C to T substitution at nucleotide position 1744, causing the arginine (R) at amino acid position 582 to be replaced by a cysteine (C). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been detected in individuals and families reported to have long QT syndrome (LQTS), or from LQTS cohorts, and has been described as a possible founder mutation in the Netherlands (Jongbloed, 1999; Nagaoka, 2008; Johnson, 2009; Hofman, 2011). This amino acid position is not well conserved in available vertebrate species. In in vitro studies, this variant has been reported to result in abnormal protein trafficking and channel function (Fougere, 2011; Perry, 2016). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
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Likely Pathogenic
(Nov 30, 2022)
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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: SCV004848873.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Arg582Cys (c.1744C>T) variant in KCNH2 has been reported in 17 individuals with Long QT Syndrome (Wilde 1999 PMID: 9973011, Tester 2005 PMID: 15840476, Tan … (more)
The p.Arg582Cys (c.1744C>T) variant in KCNH2 has been reported in 17 individuals with Long QT Syndrome (Wilde 1999 PMID: 9973011, Tester 2005 PMID: 15840476, Tan 2006 PMID: 17088455, Nemec 2003 PMID: 12877697, Nagaoka 2008 PMID: 18441445, Lupoglazoff 2001 PMID: 11222472, Kapplinger 2009 PMID: 19716085, Jongbloed 1999 PMID: 10220144, Hofman 2011 PMID: 21350584). It was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 29467). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that this variant impacts protein trafficking and function (Tseng 2007 PMID: 17293393, Fougere 2011 PMID: 21376840); however, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Long QT Syndrome. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PP3, PS3_Supporting. (less)
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Pathogenic
(Jan 01, 1999)
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no assertion criteria provided
Method: literature only
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LONG QT SYNDROME 2
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000035774.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 06, 2014 |
Comment on evidence:
In affected members of 2 Dutch families with long QT syndrome-2 (LQT2; 613688), Jongbloed et al. (1999) identified an arg582-to-cys mutation in the KCNH2 gene.
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001741590.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001958562.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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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: SCV000089490.3
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:10220144;PMID:11222472;PMID:12566525;PMID:12877697;PMID:15840476;PMID:19716085;PMID:19841300;PMID:21376840). 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:10220144;PMID:11222472;PMID:12566525;PMID:12877697;PMID:15840476;PMID:19716085;PMID:19841300;PMID:21376840). 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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Rare Coding Variants Associated With Electrocardiographic Intervals Identify Monogenic Arrhythmia Susceptibility Genes: A Multi-Ancestry Analysis. | Choi SH | Circulation. Genomic and precision medicine | 2021 | PMID: 34319147 |
Exome sequencing and characterization of 49,960 individuals in the UK Biobank. | Van Hout CV | Nature | 2020 | PMID: 33087929 |
Secondary findings in inherited heart conditions: a genotype-first feasibility study to assess phenotype, behavioural and psychosocial outcomes. | Ormondroyd E | European journal of human genetics : EJHG | 2020 | PMID: 32686758 |
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 |
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 |
Paralogous annotation of disease-causing variants in long QT syndrome genes. | Ware JS | Human mutation | 2012 | PMID: 22581653 |
Functional characterization of the LQT2-causing mutation R582C and the associated voltage-dependent fluorescence signal. | Fougere RR | Heart rhythm | 2011 | PMID: 21376840 |
Recurrent and Founder Mutations in the Netherlands: the Long-QT Syndrome. | Hofman N | Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation | 2011 | PMID: 21350584 |
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 |
Identification of a possible pathogenic link between congenital long QT syndrome and epilepsy. | Johnson JN | Neurology | 2009 | PMID: 19038855 |
Mutation site dependent variability of cardiac events in Japanese LQT2 form of congenital long-QT syndrome. | Nagaoka I | Circulation journal : official journal of the Japanese Circulation Society | 2008 | PMID: 18441445 |
Probing the outer mouth structure of the HERG channel with peptide toxin footprinting and molecular modeling. | Tseng GN | Biophysical journal | 2007 | PMID: 17293393 |
Genotype-specific onset of arrhythmias in congenital long-QT syndrome: possible therapy implications. | Tan HL | Circulation | 2006 | PMID: 17088455 |
Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing. | Tester DJ | Heart rhythm | 2005 | PMID: 15840476 |
Catecholamine-provoked microvoltage T wave alternans in genotyped long QT syndrome. | Nemec J | Pacing and clinical electrophysiology : PACE | 2003 | PMID: 12877697 |
The use of genotype-phenotype correlations in mutation analysis for the long QT syndrome. | Van Langen IM | Journal of medical genetics | 2003 | PMID: 12566525 |
Notched T waves on Holter recordings enhance detection of patients with LQt2 (HERG) mutations. | Lupoglazoff JM | Circulation | 2001 | PMID: 11222472 |
Novel KCNQ1 and HERG missense mutations in Dutch long-QT families. | Jongbloed RJ | Human mutation | 1999 | PMID: 10220144 |
Auditory stimuli as a trigger for arrhythmic events differentiate HERG-related (LQTS2) patients from KVLQT1-related patients (LQTS1). | Wilde AA | Journal of the American College of Cardiology | 1999 | PMID: 9973011 |
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Text-mined citations for rs121912508 ...
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.