Variant summary: KCNH2 c.1841C>T (p.Ala614Val) results in a non-conservative amino acid change located in the Ion transport domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250692 control chromosomes. c.1841C>T has been reported in the literature in numerous individuals affected with Long QT Syndrome. These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function, such as electrophysiological findings (Itzhaki_2011) and intracellular trafficking (Anderson_2006), both of which were impaired in the presence of the variant. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000238.4(KCNH2):c.1841C>T (p.Ala614Val)
Germline
Classification
Help
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.
(10)
Help
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.
Pathogenic
10
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000238.4(KCNH2):c.1841C>T (p.Ala614Val)
Variation ID: 29777 Accession: VCV000029777.15
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 7q36.1 7: 150951552 (GRCh38) [ NCBI UCSC ] 7: 150648640 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 4, 2013 Aug 11, 2024 Jun 17, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000238.4:c.1841C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000229.1:p.Ala614Val missense NM_001204798.2:c.821C>T NP_001191727.1:p.Ala274Val missense NM_001406753.1:c.1553C>T NP_001393682.1:p.Ala518Val missense NM_001406755.1:c.1664C>T NP_001393684.1:p.Ala555Val missense NM_001406756.1:c.1553C>T NP_001393685.1:p.Ala518Val missense NM_001406757.1:c.1541C>T NP_001393686.1:p.Ala514Val missense NM_172056.3:c.1841C>T NP_742053.1:p.Ala614Val missense NM_172057.3:c.821C>T NP_742054.1:p.Ala274Val missense NR_176254.1:n.2249C>T NR_176255.1:n.1122C>T NC_000007.14:g.150951552G>A NC_000007.13:g.150648640G>A NG_008916.1:g.31375C>T LRG_288:g.31375C>T LRG_288t1:c.1841C>T LRG_288p1:p.Ala614Val LRG_288t2:c.1841C>T LRG_288p2:p.Ala614Val LRG_288t3:c.821C>T LRG_288p3:p.Ala274Val Q12809:p.Ala614Val - Protein change
- A614V, A274V, A518V, A555V, A514V
- Other names
- -
- Canonical SPDI
- NC_000007.14:150951551:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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. |
|||
| KCNH2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3228 | 3314 | |
Conditions - Germline
| Condition
Help
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
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jun 17, 2024 | RCV000022643.29 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 13, 2022 | RCV000254785.6 | |
| not provided (1) |
no classification provided
|
- | RCV000058010.4 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Oct 21, 2022 | RCV000462085.11 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 10, 2021 | RCV002408476.2 |
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
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Sep 10, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Long QT syndrome 2
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV000263976.2
First in ClinVar: Feb 26, 2016 Last updated: Feb 26, 2016 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(May 07, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Long QT syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000917558.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: KCNH2 c.1841C>T (p.Ala614Val) results in a non-conservative amino acid change located in the Ion transport domain of the encoded protein sequence. Five of … (more)
Variant summary: KCNH2 c.1841C>T (p.Ala614Val) results in a non-conservative amino acid change located in the Ion transport domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250692 control chromosomes. c.1841C>T has been reported in the literature in numerous individuals affected with Long QT Syndrome. These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function, such as electrophysiological findings (Itzhaki_2011) and intracellular trafficking (Anderson_2006), both of which were impaired in the presence of the variant. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Oct 19, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Long QT syndrome 2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002767865.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function and dominant negative … (more)
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function and dominant negative are known mechanisms of disease for this gene. Loss of function and dominant negative are disease mechanisms for long QT syndrome 2 (MIM#613688), whereas gain of function is a disease mechanism for short QT syndrome 1 (MIM#609620). (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0112 - Variants in this gene are known to have reduced penetrance (GeneReview). (N) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine (exon 7). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in the pore forming region (PMID: 9721698). (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported in multiple patients with LQTS (ClinVar). (P) 1002 - Moderate functional evidence supporting abnormal protein function. In addition, functional studies show that this variant causes LQTS through dominant negative mechanism (PMID: 9721698, 21240260). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign (less)
|
|
|
Pathogenic
(Jan 13, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000321765.7
First in ClinVar: Oct 09, 2016 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 demonstrate a damaging effect as this variant exerts a dominant negative effect (Anderson et al., 2006; Sakaguchi et al., 2008; Itzhaki et al., 2011; Jou et al., 2013); Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 29777); This variant is associated with the following publications: (PMID: 19057127, 22949429, 27555138, 19841300, 19716085, 18441445, 25417810, 18752142, 21703926, 21367833, 19070294, 31557540, 19843919, 23303164, 16432067, 25467552, 21240260, 9544837, 9927399, 9024139, 28316956, 28718902, 23864605, 15840476, 18808722, 15090700, 19996378, 11854117, 10560244, 21295269, 21185501, 10973849, 9693036, 9721698) (less)
|
|
|
Pathogenic
(Apr 10, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002715094.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.A614V pathogenic mutation (also known as c.1841C>T), located in coding exon 7 of the KCNH2 gene, results from a C to T substitution at … (more)
The p.A614V pathogenic mutation (also known as c.1841C>T), located in coding exon 7 of the KCNH2 gene, results from a C to T substitution at nucleotide position 1841. The alanine at codon 614 is replaced by valine, an amino acid with similar properties, and is located in the H5 intramembrane pore-forming region between transmembrane helices S5 and S6. This alteration has been identified in many unrelated patients with classic long QT syndrome (LQTS), reported to co-segregate with disease, and identified as a de novo mutation in LQTS probands without familial disease (Tanaka T et al. Circulation, 1997 Feb;95:565-7; Satler CA et al. Hum. Genet., 1998 Mar;102:265-72; Splawski I et al. Genomics, 1998 Jul;51:86-97; Priori SG et al. Circulation, 1999 Feb;99:529-33; Tenenbaum M et al. Isr. Med. Assoc. J., 2008 Nov;10:809-11; Kumakura M et al. J Clin Anesth, 2016 Sep;33:81-5). Numerous functional studies have demonstrated this alteration results in prolonged action-potential duration due to the loss of function of the IKr channel by deficient intracellular protein transport to the cell surface membrane (Nakajima T et al. Circ. Res., 1998 Aug;83:415-22; Sakaguchi T et al. J. Pharmacol. Sci., 2008 Dec;108:462-71; Itzhaki I et al. Nature, 2011 Mar;471:225-9; Jou CJ et al. Circ. Res., 2013 Mar;112:826-30). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
|
|
|
Pathogenic
(Aug 30, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Congenital long QT syndrome
Affected status: yes
Allele origin:
germline
|
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000740337.1
First in ClinVar: Apr 14, 2018 Last updated: Apr 14, 2018 |
|
|
|
Pathogenic
(Oct 21, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Long QT syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000543482.6
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 16432067, 19057127, 23303164, … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 16432067, 19057127, 23303164, 25417810). 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"). ClinVar contains an entry for this variant (Variation ID: 29777). This missense change has been observed in individuals with long QT syndrome (PMID: 9024139, 9544837, 15090700, 18441445, 18808722, 19057127, 19996378, 22949429). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 614 of the KCNH2 protein (p.Ala614Val). (less)
|
|
|
Pathogenic
(Jun 17, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Long QT syndrome 2
Affected status: yes
Allele origin:
unknown
|
KardioGenetik, Herz- und Diabeteszentrum NRW
Accession: SCV005094548.1
First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024 |
Comment:
PP3moderate, PM2supporting, PP2, PM1, PS4moderate, PS3
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Mar 10, 2011)
|
no assertion criteria provided
Method: literature only
|
LONG QT SYNDROME 2
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000043932.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
Tanaka et al. (1997) identified a C-to-T transition in exon 9 of the KCNH2 gene resulting in an alanine-to-valine substitution at codon 614 (A614V) in … (more)
Tanaka et al. (1997) identified a C-to-T transition in exon 9 of the KCNH2 gene resulting in an alanine-to-valine substitution at codon 614 (A614V) in a member of a cohort of Japanese patients with long QT syndrome (LQT2; 613688). This same mutation was identified in an Israeli family with long QT syndrome by Tenenbaum et al. (2008). Itzhaki et al. (2011) developed a patient/disease-specific human induced pluripotent stem cell (iPSC) line from a patient with LQT2 due to an A614V missense mutation in the KCNH2 gene. The generated iPSCs were coaxed to differentiate into the cardiac lineage. Detailed whole-cell patch-clamp and extracellular multielectrode recordings revealed significant prolongation of the action potential duration in LQTS human iPSC-derived cardiomyocytes when compared to healthy control cells. Voltage-clamp studies confirmed that this action potential duration prolongation stems from a significant reduction of the cardiac potassium current I(Kr). Importantly, LQTS-derived cells also showed marked arrhythmogenicity, characterized by early-after depolarizations and triggered arrhythmias. Itzhaki et al. (2011) then used the LQTS human iPSC-derived cardiac tissue model to evaluate the potency of existing and novel pharmacologic agents that may either aggravate (potassium-channel blockers) or ameliorate (calcium-channel blockers, K(ATP)-channel openers, and late sodium-channel blockers) the disease phenotype. Itzhaki et al. (2011) concluded that their study illustrated the ability of human iPSC technology to model the abnormal functional phenotype of an inherited cardiac disorder and to identify potential new therapeutic agents. (less)
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Congenital long QT syndrome
Affected status: unknown
Allele origin:
germline
|
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust
Accession: SCV000089530.3
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:9024139;PMID:9544837;PMID:9693036;PMID:9927399;PMID:10560244;PMID:11854117;PMID:15840476;PMID:16432067;PMID:18441445;PMID:18752142;PMID:19057127;PMID:19716085;PMID:19841300;PMID:19843919;PMID:10187793). 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:9024139;PMID:9544837;PMID:9693036;PMID:9927399;PMID:10560244;PMID:11854117;PMID:15840476;PMID:16432067;PMID:18441445;PMID:18752142;PMID:19057127;PMID:19716085;PMID:19841300;PMID:19843919;PMID:10187793). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. (less)
|
Comment:
Comment:
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function and dominant negative are known mechanisms of disease for this gene. Loss of function and dominant negative are disease mechanisms for long QT syndrome 2 (MIM#613688), whereas gain of function is a disease mechanism for short QT syndrome 1 (MIM#609620). (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0112 - Variants in this gene are known to have reduced penetrance (GeneReview). (N) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine (exon 7). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in the pore forming region (PMID: 9721698). (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported in multiple patients with LQTS (ClinVar). (P) 1002 - Moderate functional evidence supporting abnormal protein function. In addition, functional studies show that this variant causes LQTS through dominant negative mechanism (PMID: 9721698, 21240260). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
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; Published functional studies demonstrate a damaging effect as this variant exerts a dominant negative effect (Anderson et al., 2006; Sakaguchi et al., 2008; Itzhaki et al., 2011; Jou et al., 2013); Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 29777); This variant is associated with the following publications: (PMID: 19057127, 22949429, 27555138, 19841300, 19716085, 18441445, 25417810, 18752142, 21703926, 21367833, 19070294, 31557540, 19843919, 23303164, 16432067, 25467552, 21240260, 9544837, 9927399, 9024139, 28316956, 28718902, 23864605, 15840476, 18808722, 15090700, 19996378, 11854117, 10560244, 21295269, 21185501, 10973849, 9693036, 9721698)
Comment:
The p.A614V pathogenic mutation (also known as c.1841C>T), located in coding exon 7 of the KCNH2 gene, results from a C to T substitution at nucleotide position 1841. The alanine at codon 614 is replaced by valine, an amino acid with similar properties, and is located in the H5 intramembrane pore-forming region between transmembrane helices S5 and S6. This alteration has been identified in many unrelated patients with classic long QT syndrome (LQTS), reported to co-segregate with disease, and identified as a de novo mutation in LQTS probands without familial disease (Tanaka T et al. Circulation, 1997 Feb;95:565-7; Satler CA et al. Hum. Genet., 1998 Mar;102:265-72; Splawski I et al. Genomics, 1998 Jul;51:86-97; Priori SG et al. Circulation, 1999 Feb;99:529-33; Tenenbaum M et al. Isr. Med. Assoc. J., 2008 Nov;10:809-11; Kumakura M et al. J Clin Anesth, 2016 Sep;33:81-5). Numerous functional studies have demonstrated this alteration results in prolonged action-potential duration due to the loss of function of the IKr channel by deficient intracellular protein transport to the cell surface membrane (Nakajima T et al. Circ. Res., 1998 Aug;83:415-22; Sakaguchi T et al. J. Pharmacol. Sci., 2008 Dec;108:462-71; Itzhaki I et al. Nature, 2011 Mar;471:225-9; Jou CJ et al. Circ. Res., 2013 Mar;112:826-30). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 16432067, 19057127, 23303164, 25417810). 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"). ClinVar contains an entry for this variant (Variation ID: 29777). This missense change has been observed in individuals with long QT syndrome (PMID: 9024139, 9544837, 15090700, 18441445, 18808722, 19057127, 19996378, 22949429). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 614 of the KCNH2 protein (p.Ala614Val).
Comment:
PP3moderate, PM2supporting, PP2, PM1, PS4moderate, PS3
Comment:
This variant has been reported as associated with Long QT syndrome in the following publications (PMID:9024139;PMID:9544837;PMID:9693036;PMID:9927399;PMID:10560244;PMID:11854117;PMID:15840476;PMID:16432067;PMID:18441445;PMID:18752142;PMID:19057127;PMID:19716085;PMID:19841300;PMID:19843919;PMID:10187793). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
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. |
Comment:
Variant summary: KCNH2 c.1841C>T (p.Ala614Val) results in a non-conservative amino acid change located in the Ion transport domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250692 control chromosomes. c.1841C>T has been reported in the literature in numerous individuals affected with Long QT Syndrome. These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function, such as electrophysiological findings (Itzhaki_2011) and intracellular trafficking (Anderson_2006), both of which were impaired in the presence of the variant. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function and dominant negative are known mechanisms of disease for this gene. Loss of function and dominant negative are disease mechanisms for long QT syndrome 2 (MIM#613688), whereas gain of function is a disease mechanism for short QT syndrome 1 (MIM#609620). (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0112 - Variants in this gene are known to have reduced penetrance (GeneReview). (N) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine (exon 7). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in the pore forming region (PMID: 9721698). (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported in multiple patients with LQTS (ClinVar). (P) 1002 - Moderate functional evidence supporting abnormal protein function. In addition, functional studies show that this variant causes LQTS through dominant negative mechanism (PMID: 9721698, 21240260). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
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; Published functional studies demonstrate a damaging effect as this variant exerts a dominant negative effect (Anderson et al., 2006; Sakaguchi et al., 2008; Itzhaki et al., 2011; Jou et al., 2013); Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 29777); This variant is associated with the following publications: (PMID: 19057127, 22949429, 27555138, 19841300, 19716085, 18441445, 25417810, 18752142, 21703926, 21367833, 19070294, 31557540, 19843919, 23303164, 16432067, 25467552, 21240260, 9544837, 9927399, 9024139, 28316956, 28718902, 23864605, 15840476, 18808722, 15090700, 19996378, 11854117, 10560244, 21295269, 21185501, 10973849, 9693036, 9721698)
Comment:
The p.A614V pathogenic mutation (also known as c.1841C>T), located in coding exon 7 of the KCNH2 gene, results from a C to T substitution at nucleotide position 1841. The alanine at codon 614 is replaced by valine, an amino acid with similar properties, and is located in the H5 intramembrane pore-forming region between transmembrane helices S5 and S6. This alteration has been identified in many unrelated patients with classic long QT syndrome (LQTS), reported to co-segregate with disease, and identified as a de novo mutation in LQTS probands without familial disease (Tanaka T et al. Circulation, 1997 Feb;95:565-7; Satler CA et al. Hum. Genet., 1998 Mar;102:265-72; Splawski I et al. Genomics, 1998 Jul;51:86-97; Priori SG et al. Circulation, 1999 Feb;99:529-33; Tenenbaum M et al. Isr. Med. Assoc. J., 2008 Nov;10:809-11; Kumakura M et al. J Clin Anesth, 2016 Sep;33:81-5). Numerous functional studies have demonstrated this alteration results in prolonged action-potential duration due to the loss of function of the IKr channel by deficient intracellular protein transport to the cell surface membrane (Nakajima T et al. Circ. Res., 1998 Aug;83:415-22; Sakaguchi T et al. J. Pharmacol. Sci., 2008 Dec;108:462-71; Itzhaki I et al. Nature, 2011 Mar;471:225-9; Jou CJ et al. Circ. Res., 2013 Mar;112:826-30). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 16432067, 19057127, 23303164, 25417810). 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"). ClinVar contains an entry for this variant (Variation ID: 29777). This missense change has been observed in individuals with long QT syndrome (PMID: 9024139, 9544837, 15090700, 18441445, 18808722, 19057127, 19996378, 22949429). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 614 of the KCNH2 protein (p.Ala614Val).
Comment:
PP3moderate, PM2supporting, PP2, PM1, PS4moderate, PS3
Comment:
This variant has been reported as associated with Long QT syndrome in the following publications (PMID:9024139;PMID:9544837;PMID:9693036;PMID:9927399;PMID:10560244;PMID:11854117;PMID:15840476;PMID:16432067;PMID:18441445;PMID:18752142;PMID:19057127;PMID:19716085;PMID:19841300;PMID:19843919;PMID:10187793). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Sevoflurane-associated torsade de pointes in a patient with congenital long QT syndrome genotype 2. | Kumakura M | Journal of clinical anesthesia | 2016 | PMID: 27555138 |
| Large-scale mutational analysis of Kv11.1 reveals molecular insights into type 2 long QT syndrome. | Anderson CL | Nature communications | 2014 | PMID: 25417810 |
| 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 |
| Induced pluripotent stem cell-derived cardiomyocytes and long QT syndrome: is personalized medicine ready for prime time? | Priori SG | Circulation research | 2011 | PMID: 21960720 |
| Pluripotent stem cell models of cardiac disease and their implication for drug discovery and development. | Davis RP | Trends in molecular medicine | 2011 | PMID: 21703926 |
| 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 |
| An electrifying iPSC disease model: long QT syndrome type 2 and heart cells in a dish. | Kamp TJ | Cell stem cell | 2011 | PMID: 21295269 |
| Modelling the long QT syndrome with induced pluripotent stem cells. | Itzhaki I | Nature | 2011 | PMID: 21240260 |
| Risk for life-threatening cardiac events in patients with genotype-confirmed long-QT syndrome and normal-range corrected QT intervals. | Goldenberg I | Journal of the American College of Cardiology | 2011 | PMID: 21185501 |
| Clinical characteristics and genetic background of congenital long-QT syndrome diagnosed in fetal, neonatal, and infantile life: a nationwide questionnaire survey in Japan. | Horigome H | Circulation. Arrhythmia and electrophysiology | 2010 | PMID: 19996378 |
| 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 |
| Identification of the gene causing long QT syndrome in an Israeli family. | Tenenbaum M | The Israel Medical Association journal : IMAJ | 2008 | PMID: 19070294 |
| Hydroxyzine, a first generation H(1)-receptor antagonist, inhibits human ether-a-go-go-related gene (HERG) current and causes syncope in a patient with the HERG mutation. | Sakaguchi T | Journal of pharmacological sciences | 2008 | PMID: 19057127 |
| 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 |
| Molecular genetic analysis of long QT syndrome in Norway indicating a high prevalence of heterozygous mutation carriers. | Berge KE | Scandinavian journal of clinical and laboratory investigation | 2008 | PMID: 18752142 |
| 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 |
| 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-term follow-up of notched T waves in female patients with LQT2 (HERG) mutations. | Thu-Thuy LT | Japanese heart journal | 2004 | PMID: 15090700 |
| 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 |
| Romano-Ward long QT syndrome: identification of a HERG mutation in a Taiwanese kindred. | Lee-Chen GJ | Journal of the Formosan Medical Association = Taiwan yi zhi | 1999 | PMID: 10560244 |
| Long QT syndrome-associated mutations in the Per-Arnt-Sim (PAS) domain of HERG potassium channels accelerate channel deactivation. | Chen J | The Journal of biological chemistry | 1999 | PMID: 10187793 |
| Low penetrance in the long-QT syndrome: clinical impact. | Priori SG | Circulation | 1999 | PMID: 9927399 |
| Novel mechanism of HERG current suppression in LQT2: shift in voltage dependence of HERG inactivation. | Nakajima T | Circulation research | 1998 | PMID: 9721698 |
| Genomic structure of three long QT syndrome genes: KVLQT1, HERG, and KCNE1. | Splawski I | Genomics | 1998 | PMID: 9693036 |
| Multiple different missense mutations in the pore region of HERG in patients with long QT syndrome. | Satler CA | Human genetics | 1998 | PMID: 9544837 |
| Four novel KVLQT1 and four novel HERG mutations in familial long-QT syndrome. | Tanaka T | Circulation | 1997 | PMID: 9024139 |
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Text-mined citations for rs199472944 ...
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Record 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.