ClinVar Genomic variation as it relates to human health
NM_000238.4(KCNH2):c.1810G>A (p.Gly604Ser)
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.1810G>A (p.Gly604Ser)
Variation ID: 67281 Accession: VCV000067281.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q36.1 7: 150951583 (GRCh38) [ NCBI UCSC ] 7: 150648671 (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 May 29, 2016 May 1, 2024 Jan 27, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000238.4:c.1810G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000229.1:p.Gly604Ser missense NM_001204798.2:c.790G>A NP_001191727.1:p.Gly264Ser missense NM_001406753.1:c.1522G>A NP_001393682.1:p.Gly508Ser missense NM_001406755.1:c.1633G>A NP_001393684.1:p.Gly545Ser missense NM_001406756.1:c.1522G>A NP_001393685.1:p.Gly508Ser missense NM_001406757.1:c.1510G>A NP_001393686.1:p.Gly504Ser missense NM_172056.3:c.1810G>A NP_742053.1:p.Gly604Ser missense NM_172057.3:c.790G>A NP_742054.1:p.Gly264Ser missense NR_176254.1:n.2218G>A NR_176255.1:n.1091G>A NC_000007.14:g.150951583C>T NC_000007.13:g.150648671C>T NG_008916.1:g.31344G>A LRG_288:g.31344G>A LRG_288t1:c.1810G>A LRG_288p1:p.Gly604Ser LRG_288t2:c.1810G>A LRG_288p2:p.Gly604Ser LRG_288t3:c.790G>A LRG_288p3:p.Gly264Ser Q12809:p.Gly604Ser - Protein change
- G264S, G604S, G504S, G508S, G545S
- Other names
- p.G604S:GGC>AGC
- Canonical SPDI
- NC_000007.14:150951582: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.
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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
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 |
3178 | 3260 |
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
Help
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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- | RCV000057997.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 29, 2020 | RCV000181821.5 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 27, 2024 | RCV000205578.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 25, 2020 | RCV002408563.2 |
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
(Oct 29, 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: SCV000234124.8
First in ClinVar: Jul 05, 2015 Last updated: Apr 17, 2019 |
Comment:
Reported multiple times in association with LQTS (Jongbloed et al., 1999; Splawski et al., 2000; Van Langen et al., 2003; Lupoglazoff et al., 2004; Tester … (more)
Reported multiple times in association with LQTS (Jongbloed et al., 1999; Splawski et al., 2000; Van Langen et al., 2003; Lupoglazoff et al., 2004; Tester et al., 2005; Nagaoka et al., 2008; Sato et al., 2012; Kauferstein et al., 2017); Published functional studies have demonstrated that G604S causes loss of function of the potassium channel in a dominant negative manner (Huo et al., 2008; Anderson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar as pathogenic (ClinVar Variant ID 67281; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 25417810, 18441445, 26847485, 28741726, 22821100, 10973849, 23158531, 19843919, 10220144, 18386051, 15840476, 11854117, 17171344, 19716085, 19841300, 22402334, 22949429, 27199074, 28316956, 12566525, 14998624, 28516454, 28472724, 31557540, 32661217, 31737537, 32940533) (less)
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Pathogenic
(Jan 11, 2022)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002761625.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
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Pathogenic
(Jun 25, 2020)
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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: SCV002711946.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.1810G>A (p.G604S) alteration is located in coding exon 7 of the KCNH2 gene. This alteration results from a G to A substitution at nucleotide … (more)
The c.1810G>A (p.G604S) alteration is located in coding exon 7 of the KCNH2 gene. This alteration results from a G to A substitution at nucleotide position 1810, causing the glycine (G) at amino acid position 604 to be replaced by a serine (S). Based on data from the Genome Aggregation Database (gnomAD), the KCNH2 c.1810G>A alteration was not observed, with coverage at this position. The c.1810G>A (p.G604S) alteration has been detected in multiple unrelated individuals reported to have confirmed or suspected long QT syndrome (Jongbloed, 1999; Splawski, 2000; Van Langen, 2003; Lupoglazoff, 2004; Tester, 2005; Tan, 2006; Giudicessi, 2012; Ildarova, 2012; Sato, 2012). This alteration was also reported to segregate with long QT syndrome in multiple affected members of a family (Zhang, 2007). The p.G604 amino acid is conserved in available vertebrate species. In vitro functional studies have reported this alteration to result in abnormal ion channel function and a dominant negative effect on protein trafficking (Huo, 2008; Anderson, 2014). The p.G604S 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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Pathogenic
(Jan 27, 2024)
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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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Invitae
Accession: SCV000259591.6
First in ClinVar: Jan 31, 2016 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 604 of the KCNH2 protein (p.Gly604Ser). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 604 of the KCNH2 protein (p.Gly604Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (LQT) (PMID: 10220144, 10973849, 11854117, 12566525, 14998624, 17171344, 18441445, 19843919, 22402334, 22821100, 22949429, 23158531). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 67281). 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: 18386051, 25417810). For these reasons, this variant has been classified as Pathogenic. (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: SCV000089517.3
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:10973849;PMID:11854117;PMID:12566525;PMID:14998624;PMID:15840476;PMID:17171344;PMID:18386051;PMID:18441445;PMID:19716085;PMID:19841300;PMID:22402334). 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:10973849;PMID:11854117;PMID:12566525;PMID:14998624;PMID:15840476;PMID:17171344;PMID:18386051;PMID:18441445;PMID:19716085;PMID:19841300;PMID:22402334). 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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Large-scale mutational analysis of Kv11.1 reveals molecular insights into type 2 long QT syndrome. | Anderson CL | Nature communications | 2014 | PMID: 25417810 |
Vagal reflexes following an exercise stress test: a simple clinical tool for gene-specific risk stratification in the long QT syndrome. | Crotti L | Journal of the American College of Cardiology | 2012 | PMID: 23158531 |
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 |
Long QT syndrome with nocturnal cardiac events caused by a KCNH2 missense mutation (G604S). | Sato A | Internal medicine (Tokyo, Japan) | 2012 | PMID: 22821100 |
Sodium-channel blockers might contribute to the prevention of ventricular tachycardia in patients with long QT syndrome type 2: a description of 4 cases. | Ildarova R | Journal of electrocardiology | 2012 | PMID: 22402334 |
Latent genetic backgrounds and molecular pathogenesis in drug-induced long-QT syndrome. | Itoh H | Circulation. Arrhythmia and electrophysiology | 2009 | PMID: 19843919 |
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 |
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 |
The G604S-hERG mutation alters the biophysical properties and exerts a dominant-negative effect on expression of hERG channels in HEK293 cells. | Huo J | Pflugers Archiv : European journal of physiology | 2008 | PMID: 18386051 |
A missense mutation (G604S) in the S5/pore region of HERG causes long QT syndrome in a Chinese family with a high incidence of sudden unexpected death. | Zhang Y | European journal of pediatrics | 2007 | PMID: 17171344 |
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 |
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 |
The use of genotype-phenotype correlations in mutation analysis for the long QT syndrome. | Van Langen IM | Journal of medical genetics | 2003 | PMID: 12566525 |
Increased risk of arrhythmic events in long-QT syndrome with mutations in the pore region of the human ether-a-go-go-related gene potassium channel. | Moss AJ | Circulation | 2002 | PMID: 11854117 |
Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. | Splawski I | Circulation | 2000 | PMID: 10973849 |
Novel KCNQ1 and HERG missense mutations in Dutch long-QT families. | Jongbloed RJ | Human mutation | 1999 | PMID: 10220144 |
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Text-mined citations for rs199473522 ...
HelpRecord last updated May 01, 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.