ClinVar Genomic variation as it relates to human health
NM_000238.4(KCNH2):c.1681G>A (p.Ala561Thr)
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.1681G>A (p.Ala561Thr)
Variation ID: 67229 Accession: VCV000067229.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q36.1 7: 150951712 (GRCh38) [ NCBI UCSC ] 7: 150648800 (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 Sep 16, 2024 Apr 22, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000238.4:c.1681G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000229.1:p.Ala561Thr missense NM_001204798.2:c.661G>A NP_001191727.1:p.Ala221Thr missense NM_001406753.1:c.1393G>A NP_001393682.1:p.Ala465Thr missense NM_001406755.1:c.1504G>A NP_001393684.1:p.Ala502Thr missense NM_001406756.1:c.1393G>A NP_001393685.1:p.Ala465Thr missense NM_001406757.1:c.1381G>A NP_001393686.1:p.Ala461Thr missense NM_172056.3:c.1681G>A NP_742053.1:p.Ala561Thr missense NM_172057.3:c.661G>A NP_742054.1:p.Ala221Thr missense NR_176254.1:n.2089G>A NR_176255.1:n.962G>A NC_000007.14:g.150951712C>T NC_000007.13:g.150648800C>T NG_008916.1:g.31215G>A LRG_288:g.31215G>A LRG_288t1:c.1681G>A LRG_288p1:p.Ala561Thr LRG_288t2:c.1681G>A LRG_288p2:p.Ala561Thr LRG_288t3:c.661G>A LRG_288p3:p.Ala221Thr Q12809:p.Ala561Thr - Protein change
- A221T, A561T, A461T, A502T, A465T
- Other names
- p.A561T:GCG>ACG
- Canonical SPDI
- NC_000007.14:150951711: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
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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
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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- | RCV000057939.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 22, 2024 | RCV000181805.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 19, 2019 | RCV000619406.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 19, 2022 | RCV001390277.6 |
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
(Jul 19, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001591955.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact … (more)
Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala561 amino acid residue in KCNH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7889573, 10753933, 12354768, 16432067, 18593567, 22949429, 24606995, 24623279). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 16432067, 23303164, 23470493). ClinVar contains an entry for this variant (Variation ID: 67229). This missense change has been observed in individuals with clinical features of long QT syndrome and congestive heart failure (PMID: 8877771, 10973849, 28855170). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 561 of the KCNH2 protein (p.Ala561Thr). (less)
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Pathogenic
(Jul 19, 2019)
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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: SCV000737602.5
First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024 |
Comment:
The p.A561T pathogenic mutation (also known as c.1681G>A), located in coding exon 7 of the KCNH2 gene, results from a G to A substitution at … (more)
The p.A561T pathogenic mutation (also known as c.1681G>A), located in coding exon 7 of the KCNH2 gene, results from a G to A substitution at nucleotide position 1681. The alanine at codon 561 is replaced by threonine, an amino acid with similar properties, and is located in the S5 transmembrane domain. This mutation has been reported in numerous unrelated individuals with long-QT syndrome (LQTS) and was shown to segregate with disease in a family (Dausse E et al. J Mol Cell Cardiol. 1996;28(8):1609-15; Splawski I et al. Circulation. 2000;102(10):1178-85; Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303; Matsa E et al. Eur Heart J. 2011;32(8):952-62). Functional assays have demonstrated that the mutation has a dominant negative effect on protein localization and function (Bellocq C et al. Mol Pharmacol. 2004;66(5):1093-102; Chugh SS et al. J Am Coll Cardiol. 2004;43(9):1625-9; Anderson CL et al. Circulation. 2006;113(3):365-73; Mehta A et al. Cardiovasc Res. 2014; 102(3):497-506). In addition, allele-specific knockdown of the mutant allele was able to rescue cardiomyocytes derived from a LQTS patient who was heterozygous for the p.A561T mutation (Matsa E et al. Eur Heart J. 2014;35(16):1078-87). Furthermore, other alterations in the same codon, p.A561P and p.A561V, have also been detected in patients with LQTS (Bellocq C et al. Mol. Pharmacol. 2004 Nov; 66(5):1093-102; Curran ME et al. Cell 1995 Mar; 80(5):795-803). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Apr 22, 2024)
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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: SCV000234108.12
First in ClinVar: Jul 05, 2015 Last updated: Sep 16, 2024 |
Comment:
This variant has also been reported in the heterozgyous and homozygous state in individuals with sudden cardiac death (PMID: 15120823); Published functional studies demonstrate that … (more)
This variant has also been reported in the heterozgyous and homozygous state in individuals with sudden cardiac death (PMID: 15120823); Published functional studies demonstrate that the p.(A561T) mutant channel expressed in human embryonic kidney cells failed to generate HERG current and causes defective trafficking of the KCNH2 protein to the plasma membrane (PMID: 23303164, 15120823); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28883014, 16432067, 26669661, 27761161, 18441445, 23470493, 8877771, 16379539, 28855170, 10973849, 20197117, 15828882, 10220144, 11222472, 11854117, 15280442, 19716085, 16253912, 27251404, 18808722, 21367833, 32383558, 32600061, 34546463, 31557540, 23303164, 15840476, 15120823) (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: SCV000089459.3
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:8877771;PMID:10973849;PMID:11222472;PMID:11854117;PMID:15120823;PMID:15840476;PMID:16379539;PMID:16432067;PMID:18441445;PMID:19716085). 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:8877771;PMID:10973849;PMID:11222472;PMID:11854117;PMID:15120823;PMID:15840476;PMID:16379539;PMID:16432067;PMID:18441445;PMID:19716085). 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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A Wide and Specific Spectrum of Genetic Variants and Genotype-Phenotype Correlations Revealed by Next-Generation Sequencing in Patients with Left Ventricular Noncompaction. | Wang C | Journal of the American Heart Association | 2017 | PMID: 28855170 |
Semiconductor Whole Exome Sequencing for the Identification of Genetic Variants in Colombian Patients Clinically Diagnosed with Long QT Syndrome. | Burgos M | Molecular diagnosis & therapy | 2016 | PMID: 27251404 |
Asymmetry of parental origin in long QT syndrome: preferential maternal transmission of KCNQ1 variants linked to channel dysfunction. | Itoh H | European journal of human genetics : EJHG | 2016 | PMID: 26669661 |
Re-trafficking of hERG reverses long QT syndrome 2 phenotype in human iPS-derived cardiomyocytes. | Mehta A | Cardiovascular research | 2014 | PMID: 24623279 |
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 |
Allele-specific RNA interference rescues the long-QT syndrome phenotype in human-induced pluripotency stem cell cardiomyocytes. | Matsa E | European heart journal | 2014 | PMID: 23470493 |
An in vivo cardiac assay to determine the functional consequences of putative long QT syndrome mutations. | Jou CJ | Circulation research | 2013 | PMID: 23303164 |
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 |
Drug evaluation in cardiomyocytes derived from human induced pluripotent stem cells carrying a long QT syndrome type 2 mutation. | Matsa E | European heart journal | 2011 | PMID: 21367833 |
Congenital long QT syndrome and 2:1 atrioventricular block: an optimistic outcome in the current era. | Aziz PF | Heart rhythm | 2010 | PMID: 20197117 |
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 |
Protective effect of KCNH2 single nucleotide polymorphism K897T in LQTS families and identification of novel KCNQ1 and KCNH2 mutations. | Zhang X | BMC medical genetics | 2008 | PMID: 18808722 |
Functional studies on three novel HCNH2 mutations in Taiwan: identification of distinct mechanisms of channel defect and dissociation between glycosylation defect and assembly defect. | Hsueh CH | Biochemical and biophysical research communications | 2008 | PMID: 18593567 |
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 |
Most LQT2 mutations reduce Kv11.1 (hERG) current by a class 2 (trafficking-deficient) mechanism. | Anderson CL | Circulation | 2006 | PMID: 16432067 |
Gene sequencing in neonates and infants with the long QT syndrome. | Shim SH | Genetic testing | 2005 | PMID: 16379539 |
Targeted mutational analysis of ankyrin-B in 541 consecutive, unrelated patients referred for long QT syndrome genetic testing and 200 healthy subjects. | Sherman J | Heart rhythm | 2005 | PMID: 16253912 |
Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing. | Tester DJ | Heart rhythm | 2005 | PMID: 15840476 |
A common antitussive drug, clobutinol, precipitates the long QT syndrome 2. | Bellocq C | Molecular pharmacology | 2004 | PMID: 15280442 |
Postmortem molecular screening in unexplained sudden death. | Chugh SS | Journal of the American College of Cardiology | 2004 | PMID: 15120823 |
A novel mutation (T65P) in the PAS domain of the human potassium channel HERG results in the long QT syndrome by trafficking deficiency. | Paulussen A | The Journal of biological chemistry | 2002 | PMID: 12354768 |
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 |
Notched T waves on Holter recordings enhance detection of patients with LQt2 (HERG) mutations. | Lupoglazoff JM | Circulation | 2001 | PMID: 11222472 |
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 |
A mutation in HERG associated with notched T waves in long QT syndrome. | Dausse E | Journal of molecular and cellular cardiology | 1996 | PMID: 8877771 |
A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. | Curran ME | Cell | 1995 | PMID: 7889573 |
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Text-mined citations for rs199472921 ...
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.