ClinVar Genomic variation as it relates to human health
NM_000238.4(KCNH2):c.3040C>T (p.Arg1014Ter)
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.3040C>T (p.Arg1014Ter)
Variation ID: 200518 Accession: VCV000200518.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q36.1 7: 150947440 (GRCh38) [ NCBI UCSC ] 7: 150644528 (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 Jun 3, 2016 Feb 28, 2024 Oct 22, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000238.4:c.3040C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000229.1:p.Arg1014Ter nonsense NM_172057.3:c.2020C>T NP_742054.1:p.Arg674Ter nonsense NC_000007.14:g.150947440G>A NC_000007.13:g.150644528G>A NG_008916.1:g.35487C>T LRG_288:g.35487C>T LRG_288t1:c.3040C>T LRG_288p1:p.Arg1014Ter - Protein change
- R1014*, R674*
- Other names
- p.R1014*:CGA>TGA
- Canonical SPDI
- NC_000007.14:150947439: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.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
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
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 |
3048 | 3130 |
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 (2) |
criteria provided, multiple submitters, no conflicts
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Oct 22, 2023 | RCV000204945.10 | |
Pathogenic (2) |
criteria provided, single submitter
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Nov 13, 2019 | RCV000223784.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 2, 2022 | RCV002272162.2 |
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
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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
(Feb 02, 2022)
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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:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557763.1
First in ClinVar: Aug 08, 2022 Last updated: Aug 08, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with Long QT syndrome 2 (LQTS; MIM#613688). Gain of function is also a known mechanism associated with Short QT syndrome 1 (MIM#609620) (OMIM, PMID: 10753933; PMID: 21777565). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 20301308). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many other variants predicted to cause NMD have been reported as pathogenic in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with LQTS (ClinVar, PMID: 10973849, PMID: 30847666). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Sep 12, 2022)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002598583.1
First in ClinVar: Nov 05, 2022 Last updated: Nov 05, 2022 |
Comment:
Variant summary: KCNH2 c.3040C>T (p.Arg1014X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: KCNH2 c.3040C>T (p.Arg1014X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 165078 control chromosomes. c.3040C>T has been reported in the literature in multiple individuals affected with Long QT Syndrome (example Splawski_2000, Lieve_2013, Westphal _2020). These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant causes HERG channel dysfunction by defective trafficking of the mutant protein (Gong_2004). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Oct 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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Invitae
Accession: SCV000260318.8
First in ClinVar: Jan 31, 2016 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg1014*) in the KCNH2 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg1014*) in the KCNH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KCNH2 are known to be pathogenic (PMID: 10973849, 19862833). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with severe and mild long QT syndrome (PMID: 10973849, 14642687). ClinVar contains an entry for this variant (Variation ID: 200518). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 13, 2019)
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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: SCV000234210.8
First in ClinVar: Jul 05, 2015 Last updated: Apr 17, 2019 |
Comment:
Reported in association with LQTS (Splawski et al., 2000; Gong et al., 2004; Tester et al., 2005); Reported in ClinVar as pathogenic (ClinVar Variant ID# … (more)
Reported in association with LQTS (Splawski et al., 2000; Gong et al., 2004; Tester et al., 2005); Reported in ClinVar as pathogenic (ClinVar Variant ID# 200518; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published mRNA functional studies demonstrate a damaging effect as this variant is shown to lead to a reduced level of mutant mRNA compared to that of the wild-type allele; therefore, the authors concluded that absence of R1014X protein product due to nonsense mediated mRNA decay causes loss of normal protein function (Gong et al., 2007); Additional functional studies demonstrate that this variant leads to a reduction of surface channel expression (Puckerin et al., 2016); This variant is associated with the following publications: (PMID: 15572053, 10973849, 19324319, 17576861, 26775140, 18675227, 15958262, 21419236, 15840476, 19716085, 14642687, 31737537, 30847666) (less)
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Pathogenic
(Mar 24, 2011)
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no assertion criteria provided
Method: clinical testing
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Not provided
Affected status: not provided
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000280127.1
First in ClinVar: Jun 03, 2016 Last updated: Jun 03, 2016 |
Comment:
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case … (more)
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease (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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Long QT Syndrome Overview. | Adam MP | - | 2024 | PMID: 20301308 |
Reclassification of genetic variants in children with long QT syndrome. | Westphal DS | Molecular genetics & genomic medicine | 2020 | PMID: 32383558 |
Large next-generation sequencing gene panels in genetic heart disease: yield of pathogenic variants and variants of unknown significance. | van Lint FHM | Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation | 2019 | PMID: 30847666 |
Results of genetic testing in 855 consecutive unrelated patients referred for long QT syndrome in a clinical laboratory. | Lieve KV | Genetic testing and molecular biomarkers | 2013 | PMID: 23631430 |
The hERG K(+) channel S4 domain L532P mutation: characterization at 37°C. | Zhang YH | Biochimica et biophysica acta | 2011 | PMID: 21777565 |
The genetic basis of long QT and short QT syndromes: a mutation update. | Hedley PL | Human mutation | 2009 | PMID: 19862833 |
Defective assembly and trafficking of mutant HERG channels with C-terminal truncations in long QT syndrome. | Gong Q | Journal of molecular and cellular cardiology | 2004 | PMID: 15572053 |
A new oral therapy for long QT syndrome: long-term oral potassium improves repolarization in patients with HERG mutations. | Etheridge SP | Journal of the American College of Cardiology | 2003 | PMID: 14642687 |
Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. | Splawski I | Circulation | 2000 | PMID: 10973849 |
The dominant negative LQT2 mutation A561V reduces wild-type HERG expression. | Kagan A | The Journal of biological chemistry | 2000 | PMID: 10753933 |
Text-mined citations for rs794728403 ...
HelpRecord last updated Mar 05, 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.