This premature translational stop signal has been observed in individual(s) with long QT syndrome (PMID: 11802537, 19841298, 26704558). In at least one individual the variant was observed to be de novo. 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 creates a premature translational stop signal (p.Arg744*) 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). ClinVar contains an entry for this variant (Variation ID: 180383). For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000238.4(KCNH2):c.2230C>T (p.Arg744Ter)
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.
(9)
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
9
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.2230C>T (p.Arg744Ter)
Variation ID: 180383 Accession: VCV000180383.20
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 7q36.1 7: 150950336 (GRCh38) [ NCBI UCSC ] 7: 150647424 (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 Feb 7, 2015 Sep 16, 2024 May 29, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000238.4:c.2230C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000229.1:p.Arg744Ter nonsense NM_001204798.2:c.1210C>T NP_001191727.1:p.Arg404Ter nonsense NM_001406753.1:c.1942C>T NP_001393682.1:p.Arg648Ter nonsense NM_001406755.1:c.2053C>T NP_001393684.1:p.Arg685Ter nonsense NM_001406756.1:c.1942C>T NP_001393685.1:p.Arg648Ter nonsense NM_001406757.1:c.1930C>T NP_001393686.1:p.Arg644Ter nonsense NM_172056.3:c.2230C>T NP_742053.1:p.Arg744Ter nonsense NM_172057.3:c.1210C>T NP_742054.1:p.Arg404Ter nonsense NR_176254.1:n.2638C>T NR_176255.1:n.1511C>T NC_000007.14:g.150950336G>A NC_000007.13:g.150647424G>A NG_008916.1:g.32591C>T LRG_288:g.32591C>T LRG_288t1:c.2230C>T LRG_288p1:p.Arg744Ter LRG_288t2:c.2230C>T LRG_288p2:p.Arg744Ter LRG_288t3:c.1210C>T LRG_288p3:p.Arg404Ter - Protein change
- R404*, R744*, R648*, R644*, R685*
- Other names
-
p.R744*:CGA>TGA
- Canonical SPDI
- NC_000007.14:150950335: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.
-
0.00040 (C)
-
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 |
3223 | 3309 | |
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
|
May 23, 2023 | RCV000157266.8 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 29, 2024 | RCV000181843.6 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 8, 2024 | RCV000473013.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 5, 2020 | RCV000617781.4 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 25, 2018 | RCV004017439.1 |
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
(Jun 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Long QT syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000543429.7
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
This premature translational stop signal has been observed in individual(s) with long QT syndrome (PMID: 11802537, 19841298, 26704558). In at least one individual the variant … (more)
This premature translational stop signal has been observed in individual(s) with long QT syndrome (PMID: 11802537, 19841298, 26704558). In at least one individual the variant was observed to be de novo. 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 creates a premature translational stop signal (p.Arg744*) 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). ClinVar contains an entry for this variant (Variation ID: 180383). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Nov 05, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000737741.5
First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024 |
Comment:
The p.R744* pathogenic mutation (also known as c.2230C>T), located in coding exon 9 of the KCNH2 gene, results from a C to T substitution at … (more)
The p.R744* pathogenic mutation (also known as c.2230C>T), located in coding exon 9 of the KCNH2 gene, results from a C to T substitution at nucleotide position 2230. This changes the amino acid from an arginine to a stop codon within coding exon 9. This alteration has been detected in individuals with long QT syndrome (LQTS) as well as in LQTS genetic testing cohorts, and has shown segregation with disease in two families (Ko YL et al. J. Formos. Med. Assoc., 2001 Nov;100:767-71; Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303; Schwartz PJ et al. Circulation, 2009 Nov;120:1761-7). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
|
|
|
Pathogenic
(Aug 06, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Long QT syndrome 2
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002579514.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PVS1, PS2, PM2_SUP, PP1
|
Number of individuals with the variant: 1
Sex: female
|
|
|
Pathogenic
(Jan 08, 2024)
|
criteria provided, single submitter
Method: research
|
Long QT syndrome
Affected status: yes
Allele origin:
maternal
|
Dept of Medical Biology, Uskudar University
Accession: SCV004021972.2
First in ClinVar: Jul 29, 2023 Last updated: Jan 26, 2024 |
Comment:
Criteria: PVS1_Strong, PP1_Strong, PM2
Number of individuals with the variant: 3
Sex: male
Ethnicity/Population group: Turkish
Geographic origin: Turkey
|
|
|
Pathogenic
(Jul 25, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Congenital long QT syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848134.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Arg744X variant in KCNH2 has been reported in 1 Caucasian individual with sudden unexpected death in epilepsy (Bagnall 2016), 8 individuals with Long QT … (more)
The p.Arg744X variant in KCNH2 has been reported in 1 Caucasian individual with sudden unexpected death in epilepsy (Bagnall 2016), 8 individuals with Long QT syndrome (Ko 2001, Moss 2002, Schwartz 2009, Kapplinger 2009, Crotti 2012), and 1 individual with LQTS and Charcot-Marie-Tooth disease, who also carried a dup of 17p11.2 (Losito 2009). This variant segregated with LQTS in 13 relatives from multiple families. This variant has also been reported in ClinVar (Variation ID 180383) and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 744, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the KCNH2 gene is an established disease mechanism in LQTS. In summary, this variant meets criteria to be classified as pathogenic for LQTS in an autosomal dominant manner based upon segregation studies, absence from controls, and predicted impact on protein. ACMG/AMP Criteria applied: PVS1, PP1_Strong, PM2, PS4_Moderate (Richards 2015). (less)
|
|
|
Pathogenic
(Jun 25, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Long QT syndrome 2
Affected status: yes
Allele origin:
unknown
|
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues
Accession: SCV002320699.1
First in ClinVar: Apr 08, 2022 Last updated: Apr 08, 2022 |
|
|
|
Pathogenic
(May 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Long QT syndrome 2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV003925753.1
First in ClinVar: May 27, 2023 Last updated: May 27, 2023 |
Clinical Features:
Palpitations (present) , Prolonged QTc interval (present) , Dermoid cyst (present) , Superior oblique muscle restriction (present)
|
|
|
Pathogenic
(May 29, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000234146.10
First in ClinVar: Jul 05, 2015 Last updated: Sep 16, 2024 |
Comment:
Reported in patients with LQTS, prolonged QT intervals, and an individual with sudden unexpected death in epilepsy (PMID: 19841298, 22338672, 26704558); also identified in patients … (more)
Reported in patients with LQTS, prolonged QT intervals, and an individual with sudden unexpected death in epilepsy (PMID: 19841298, 22338672, 26704558); also identified in patients with LQTS referred for genetic testing at GeneDx; Segregates with disease in many affected individuals from several families in published literature (PMID: 22338672, 11802537); Not observed at significant frequency in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 19716085, 28363160, 11802537, 22338672, 11854117, 26704558, 28775708, 25525159, 31727422, 33304416, 33013630, 31018519, 34546463, 36861347, 19841298) (less)
|
|
|
Pathogenic
(Aug 29, 2014)
|
no assertion criteria provided
Method: clinical testing
|
Long QT syndrome 2
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV000206996.1
First in ClinVar: Feb 07, 2015 Last updated: Feb 07, 2015 |
Number of individuals with the variant: 1
|
Comment:
Comment:
The p.R744* pathogenic mutation (also known as c.2230C>T), located in coding exon 9 of the KCNH2 gene, results from a C to T substitution at nucleotide position 2230. This changes the amino acid from an arginine to a stop codon within coding exon 9. This alteration has been detected in individuals with long QT syndrome (LQTS) as well as in LQTS genetic testing cohorts, and has shown segregation with disease in two families (Ko YL et al. J. Formos. Med. Assoc., 2001 Nov;100:767-71; Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303; Schwartz PJ et al. Circulation, 2009 Nov;120:1761-7). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Comment:
Criteria: PVS1_Strong, PP1_Strong, PM2
Comment:
The p.Arg744X variant in KCNH2 has been reported in 1 Caucasian individual with sudden unexpected death in epilepsy (Bagnall 2016), 8 individuals with Long QT syndrome (Ko 2001, Moss 2002, Schwartz 2009, Kapplinger 2009, Crotti 2012), and 1 individual with LQTS and Charcot-Marie-Tooth disease, who also carried a dup of 17p11.2 (Losito 2009). This variant segregated with LQTS in 13 relatives from multiple families. This variant has also been reported in ClinVar (Variation ID 180383) and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 744, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the KCNH2 gene is an established disease mechanism in LQTS. In summary, this variant meets criteria to be classified as pathogenic for LQTS in an autosomal dominant manner based upon segregation studies, absence from controls, and predicted impact on protein. ACMG/AMP Criteria applied: PVS1, PP1_Strong, PM2, PS4_Moderate (Richards 2015).
Comment:
Reported in patients with LQTS, prolonged QT intervals, and an individual with sudden unexpected death in epilepsy (PMID: 19841298, 22338672, 26704558); also identified in patients with LQTS referred for genetic testing at GeneDx; Segregates with disease in many affected individuals from several families in published literature (PMID: 22338672, 11802537); Not observed at significant frequency in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 19716085, 28363160, 11802537, 22338672, 11854117, 26704558, 28775708, 25525159, 31727422, 33304416, 33013630, 31018519, 34546463, 36861347, 19841298)
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:
This premature translational stop signal has been observed in individual(s) with long QT syndrome (PMID: 11802537, 19841298, 26704558). In at least one individual the variant was observed to be de novo. 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 creates a premature translational stop signal (p.Arg744*) 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). ClinVar contains an entry for this variant (Variation ID: 180383). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.R744* pathogenic mutation (also known as c.2230C>T), located in coding exon 9 of the KCNH2 gene, results from a C to T substitution at nucleotide position 2230. This changes the amino acid from an arginine to a stop codon within coding exon 9. This alteration has been detected in individuals with long QT syndrome (LQTS) as well as in LQTS genetic testing cohorts, and has shown segregation with disease in two families (Ko YL et al. J. Formos. Med. Assoc., 2001 Nov;100:767-71; Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303; Schwartz PJ et al. Circulation, 2009 Nov;120:1761-7). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Comment:
Criteria: PVS1_Strong, PP1_Strong, PM2
Comment:
The p.Arg744X variant in KCNH2 has been reported in 1 Caucasian individual with sudden unexpected death in epilepsy (Bagnall 2016), 8 individuals with Long QT syndrome (Ko 2001, Moss 2002, Schwartz 2009, Kapplinger 2009, Crotti 2012), and 1 individual with LQTS and Charcot-Marie-Tooth disease, who also carried a dup of 17p11.2 (Losito 2009). This variant segregated with LQTS in 13 relatives from multiple families. This variant has also been reported in ClinVar (Variation ID 180383) and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 744, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the KCNH2 gene is an established disease mechanism in LQTS. In summary, this variant meets criteria to be classified as pathogenic for LQTS in an autosomal dominant manner based upon segregation studies, absence from controls, and predicted impact on protein. ACMG/AMP Criteria applied: PVS1, PP1_Strong, PM2, PS4_Moderate (Richards 2015).
Comment:
Reported in patients with LQTS, prolonged QT intervals, and an individual with sudden unexpected death in epilepsy (PMID: 19841298, 22338672, 26704558); also identified in patients with LQTS referred for genetic testing at GeneDx; Segregates with disease in many affected individuals from several families in published literature (PMID: 22338672, 11802537); Not observed at significant frequency in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 19716085, 28363160, 11802537, 22338672, 11854117, 26704558, 28775708, 25525159, 31727422, 33304416, 33013630, 31018519, 34546463, 36861347, 19841298)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Exome-based analysis of cardiac arrhythmia, respiratory control, and epilepsy genes in sudden unexpected death in epilepsy. | Bagnall RD | Annals of neurology | 2016 | PMID: 26704558 |
| The genetic basis of long QT and short QT syndromes: a mutation update. | Hedley PL | Human mutation | 2009 | PMID: 19862833 |
| Prevalence of the congenital long-QT syndrome. | Schwartz PJ | Circulation | 2009 | PMID: 19841298 |
| 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 |
| Linkage and mutation analysis in two Taiwanese families with long QT syndrome. | Ko YL | Journal of the Formosan Medical Association = Taiwan yi zhi | 2001 | PMID: 11802537 |
| Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. | Splawski I | Circulation | 2000 | PMID: 10973849 |
Text-mined citations for rs189014161 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
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.