This sequence change creates a premature translational stop signal (p.Trp1001*) 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 Long QT syndrome (PMID: 17576861, 19716085, 26669661). ClinVar contains an entry for this variant (Variation ID: 200513). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000238.4(KCNH2):c.3002G>A (p.Trp1001Ter)
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.
(6)
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
6
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.3002G>A (p.Trp1001Ter)
Variation ID: 200513 Accession: VCV000200513.20
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 7q36.1 7: 150947478 (GRCh38) [ NCBI UCSC ] 7: 150644566 (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 May 29, 2016 Sep 16, 2024 Jul 30, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000238.4:c.3002G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000229.1:p.Trp1001Ter nonsense NM_001406753.1:c.2714G>A NP_001393682.1:p.Trp905Ter nonsense NM_172057.3:c.1982G>A NP_742054.1:p.Trp661Ter nonsense NR_176254.1:n.3223G>A non-coding transcript variant NR_176255.1:n.2096G>A non-coding transcript variant NC_000007.14:g.150947478C>T NC_000007.13:g.150644566C>T NG_008916.1:g.35449G>A LRG_288:g.35449G>A LRG_288t1:c.3002G>A LRG_288p1:p.Trp1001Ter LRG_288t3:c.1982G>A LRG_288p3:p.Trp661Ter - Protein change
- W1001*, W661*, W905*
- Other names
-
p.W1001*:TGG>TAG
- Canonical SPDI
- NC_000007.14:150947477:C:T
-
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 |
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 (1) |
criteria provided, single submitter
|
Sep 26, 2022 | RCV000181904.14 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jul 30, 2024 | RCV000228852.18 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 15, 2019 | RCV001842834.10 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 19, 2019 | RCV002433796.9 |
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 29, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Long QT syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000283980.8
First in ClinVar: Jul 01, 2016 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Trp1001*) 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.Trp1001*) 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 Long QT syndrome (PMID: 17576861, 19716085, 26669661). ClinVar contains an entry for this variant (Variation ID: 200513). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Nov 15, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiac arrhythmia
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV001357071.2
First in ClinVar: Jun 22, 2020 Last updated: Jan 15, 2022 |
Comment:
This variant changes 1 nucleotide in exon 13 of the KCNH2 gene, creating a premature translation stop signal. This variant is expected to result in … (more)
This variant changes 1 nucleotide in exon 13 of the KCNH2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with long QT syndrome (PMID: 19716085, 26846766). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of KCNH2 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. (less)
|
|
|
Pathogenic
(Sep 26, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000234207.12
First in ClinVar: Jul 05, 2015 Last updated: Apr 23, 2023 |
Comment:
Identified in patients with LQTS referred for genetic testing at GeneDx and in published literature (Kapplinger et al., 2009; Neubauer et al., 2016; Itoh et … (more)
Identified in patients with LQTS referred for genetic testing at GeneDx and in published literature (Kapplinger et al., 2009; Neubauer et al., 2016; Itoh et al., 2016); 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: 11854117, 19716085, 28410642, 27807201, 23995044, 26669661, 24363251, 17576861, 26846766) (less)
|
|
|
Pathogenic
(Mar 19, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002750786.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.W1001* pathogenic mutation (also known as c.3002G>A), located in coding exon 13 of the KCNH2 gene, results from a G to A substitution at … (more)
The p.W1001* pathogenic mutation (also known as c.3002G>A), located in coding exon 13 of the KCNH2 gene, results from a G to A substitution at nucleotide position 3002. This changes the amino acid from a tryptophan to a stop codon within coding exon 13. In a study of long QT syndrome clinical genetic testing, this alteration was reported in five individuals; however, clinical details were limited (Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303). In addition to the 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
(Jul 30, 2024)
|
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: SCV005202229.1
First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024 |
Comment:
Variant summary: KCNH2 c.3002G>A (p.Trp1001X) 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.3002G>A (p.Trp1001X) 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 frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.3002G>A has been reported in the literature in multiple individuals affected with Long QT Syndrome (e.g. Kim_2010). These data indicate that the variant is very likely to be associated with disease. The following publication have been ascertained in the context of this evaluation (PMID: 20850565). ClinVar contains an entry for this variant (Variation ID: 200513). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
not provided
(-)
|
no classification provided
Method: phenotyping only
|
Long QT syndrome
Affected status: yes
Allele origin:
unknown
|
GenomeConnect, ClinGen
Accession: SCV002818324.1
First in ClinVar: Jan 07, 2023 Last updated: Jan 07, 2023 |
Comment:
Variant classified as Pathogenic and reported on 12-17-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided … (more)
Variant classified as Pathogenic and reported on 12-17-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Myopia (present) , Hypermetropia (present) , Tinnitus (present) , Bipolar affective disorder (present) , Motor stereotypies (present) , Abnormal aggressive, impulsive or violent behavior (present) … (more)
Myopia (present) , Hypermetropia (present) , Tinnitus (present) , Bipolar affective disorder (present) , Motor stereotypies (present) , Abnormal aggressive, impulsive or violent behavior (present) , Anxiety (present) , Depression (present) , Delusion (present) , Hallucinations (present) , Psychotic disorder (present) , Short attention span (present) , Abnormal limb bone morphology (present) , Joint hypermobility (present) , Cardiac arrhythmia (present) , Abnormal EKG (present) , Abnormality of the cardiovascular system (present) , Abnormal cardiovascular system morphology (present) (less)
Indication for testing: Family Testing
Age: 10-19 years
Sex: female
Method: Familial/Targeted Variant Analysis
Testing laboratory: GeneDx
Date variant was reported to submitter: 2018-12-17
Testing laboratory interpretation: Pathogenic
|
Comment:
Comment:
This variant changes 1 nucleotide in exon 13 of the KCNH2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with long QT syndrome (PMID: 19716085, 26846766). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of KCNH2 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic.
Comment:
Identified in patients with LQTS referred for genetic testing at GeneDx and in published literature (Kapplinger et al., 2009; Neubauer et al., 2016; Itoh et al., 2016); 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: 11854117, 19716085, 28410642, 27807201, 23995044, 26669661, 24363251, 17576861, 26846766)
Comment:
The p.W1001* pathogenic mutation (also known as c.3002G>A), located in coding exon 13 of the KCNH2 gene, results from a G to A substitution at nucleotide position 3002. This changes the amino acid from a tryptophan to a stop codon within coding exon 13. In a study of long QT syndrome clinical genetic testing, this alteration was reported in five individuals; however, clinical details were limited (Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303). In addition to the 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:
Variant summary: KCNH2 c.3002G>A (p.Trp1001X) 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 frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.3002G>A has been reported in the literature in multiple individuals affected with Long QT Syndrome (e.g. Kim_2010). These data indicate that the variant is very likely to be associated with disease. The following publication have been ascertained in the context of this evaluation (PMID: 20850565). ClinVar contains an entry for this variant (Variation ID: 200513). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Variant classified as Pathogenic and reported on 12-17-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
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 sequence change creates a premature translational stop signal (p.Trp1001*) 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 Long QT syndrome (PMID: 17576861, 19716085, 26669661). ClinVar contains an entry for this variant (Variation ID: 200513). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant changes 1 nucleotide in exon 13 of the KCNH2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with long QT syndrome (PMID: 19716085, 26846766). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of KCNH2 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic.
Comment:
Identified in patients with LQTS referred for genetic testing at GeneDx and in published literature (Kapplinger et al., 2009; Neubauer et al., 2016; Itoh et al., 2016); 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: 11854117, 19716085, 28410642, 27807201, 23995044, 26669661, 24363251, 17576861, 26846766)
Comment:
The p.W1001* pathogenic mutation (also known as c.3002G>A), located in coding exon 13 of the KCNH2 gene, results from a G to A substitution at nucleotide position 3002. This changes the amino acid from a tryptophan to a stop codon within coding exon 13. In a study of long QT syndrome clinical genetic testing, this alteration was reported in five individuals; however, clinical details were limited (Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303). In addition to the 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:
Variant summary: KCNH2 c.3002G>A (p.Trp1001X) 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 frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.3002G>A has been reported in the literature in multiple individuals affected with Long QT Syndrome (e.g. Kim_2010). These data indicate that the variant is very likely to be associated with disease. The following publication have been ascertained in the context of this evaluation (PMID: 20850565). ClinVar contains an entry for this variant (Variation ID: 200513). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Variant classified as Pathogenic and reported on 12-17-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
| Trigger-specific risk factors and response to therapy in long QT syndrome type 2. | Kim JA | Heart rhythm | 2010 | PMID: 20850565 |
| The genetic basis of long QT and short QT syndromes: a mutation update. | Hedley PL | Human mutation | 2009 | PMID: 19862833 |
| 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 |
| Nonsense mutations in hERG cause a decrease in mutant mRNA transcripts by nonsense-mediated mRNA decay in human long-QT syndrome. | Gong Q | Circulation | 2007 | PMID: 17576861 |
| Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. | Splawski I | Circulation | 2000 | PMID: 10973849 |
Text-mined citations for rs794728401 ...
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 Nov 10, 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.