This missense variant replaces alanine with valine at codon 715 of the KCNH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study showed that this variant had similar expression compared to wild type (PMID: 26958806). This variant has been reported in individuals affected with long QT syndrome. However, those individuals have other long QT syndrome related co-variants (PMID: 23174487). This variant has been identified in 8/282710 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
ClinVar Genomic variation as it relates to human health
NM_000238.4(KCNH2):c.2144C>T (p.Ala715Val)
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.
(5)
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.
Uncertain significance
5
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.2144C>T (p.Ala715Val)
Variation ID: 200413 Accession: VCV000200413.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q36.1 7: 150950922 (GRCh38) [ NCBI UCSC ] 7: 150648010 (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 9, 2017 May 1, 2024 Oct 2, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000238.4:c.2144C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000229.1:p.Ala715Val missense NM_001204798.2:c.1124C>T NP_001191727.1:p.Ala375Val missense NM_001406753.1:c.1856C>T NP_001393682.1:p.Ala619Val missense NM_001406755.1:c.1967C>T NP_001393684.1:p.Ala656Val missense NM_001406756.1:c.1856C>T NP_001393685.1:p.Ala619Val missense NM_001406757.1:c.1844C>T NP_001393686.1:p.Ala615Val missense NM_172056.3:c.2144C>T NP_742053.1:p.Ala715Val missense NM_172057.3:c.1124C>T NP_742054.1:p.Ala375Val missense NR_176254.1:n.2552C>T NR_176255.1:n.1425C>T NC_000007.14:g.150950922G>A NC_000007.13:g.150648010G>A NG_008916.1:g.32005C>T LRG_288:g.32005C>T LRG_288t1:c.2144C>T LRG_288p1:p.Ala715Val LRG_288t2:c.2144C>T LRG_288p2:p.Ala715Val LRG_288t3:c.1124C>T LRG_288p3:p.Ala375Val - Protein change
- A375V, A715V, A615V, A619V, A656V
- Other names
- -
- Canonical SPDI
- NC_000007.14:150950921:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00003
- 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. |
|---|---|---|---|---|
| Uncertain significance (1) |
criteria provided, single submitter
|
Mar 31, 2016 | RCV000454933.12 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Nov 7, 2016 | RCV000621645.11 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 2, 2023 | RCV001042787.17 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Dec 6, 2022 | RCV001842827.11 |
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. |
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|---|---|---|---|---|---|
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Uncertain significance
(Dec 06, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiac arrhythmia
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV001355817.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces alanine with valine at codon 715 of the KCNH2 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces alanine with valine at codon 715 of the KCNH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study showed that this variant had similar expression compared to wild type (PMID: 26958806). This variant has been reported in individuals affected with long QT syndrome. However, those individuals have other long QT syndrome related co-variants (PMID: 23174487). This variant has been identified in 8/282710 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
|
|
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Uncertain significance
(Jul 29, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Long QT syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001206491.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 20, 2024 |
Comment:
Experimental studies have shown that this missense change does not substantially affect KCNH2 function (PMID: 26958806). This sequence change replaces alanine, which is neutral and … (more)
Experimental studies have shown that this missense change does not substantially affect KCNH2 function (PMID: 26958806). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 715 of the KCNH2 protein (p.Ala715Val). This variant is present in population databases (rs780656919, gnomAD 0.01%). This missense change has been observed in individual(s) with long QT syndrome (LQTS) (PMID: 23174487). ClinVar contains an entry for this variant (Variation ID: 200413). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
|
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Uncertain significance
(Nov 07, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000737778.5
First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024 |
Comment:
The p.A715V variant (also known as c.2144C>T), located in coding exon 8 of the KCNH2 gene, results from a C to T substitution at nucleotide … (more)
The p.A715V variant (also known as c.2144C>T), located in coding exon 8 of the KCNH2 gene, results from a C to T substitution at nucleotide position 2144. The alanine at codon 715 is replaced by valine, an amino acid with similar properties. This alteration was detected in a long QT syndrome (LQTS) cohort; however, the patients harbored multiple LQTS alterations and clinical data was not provided (Mullally J et al. Heart Rhythm. 2013;10:378-82). This variant was previously reported in the SNP database (dbSNP) as rs780656919. Based on data from ExAC, the T allele has an overall frequency of less than 0.01% (1/105914). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
|
|
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Uncertain significance
(Mar 31, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000539433.1
First in ClinVar: Apr 09, 2017 Last updated: Apr 09, 2017 |
Comment:
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or … (more)
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: No predicted splice impact; 1 paper in HGMD; ExAC: 2/66498 European; ClinVar: 1 VUS (less)
Method: Genome/Exome Filtration
|
|
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Uncertain Significance
(Oct 02, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Long QT syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004843925.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Comment:
This missense variant replaces alanine with valine at codon 715 of the KCNH2 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces alanine with valine at codon 715 of the KCNH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study showed that this variant had similar expression compared to wild type (PMID: 26958806). This variant has been reported in individuals affected with long QT syndrome. However, those individuals have other long QT syndrome related co-variants (PMID: 23174487). This variant has been identified in 8/282710 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 4
|
Comment:
Comment:
Experimental studies have shown that this missense change does not substantially affect KCNH2 function (PMID: 26958806). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 715 of the KCNH2 protein (p.Ala715Val). This variant is present in population databases (rs780656919, gnomAD 0.01%). This missense change has been observed in individual(s) with long QT syndrome (LQTS) (PMID: 23174487). ClinVar contains an entry for this variant (Variation ID: 200413). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
The p.A715V variant (also known as c.2144C>T), located in coding exon 8 of the KCNH2 gene, results from a C to T substitution at nucleotide position 2144. The alanine at codon 715 is replaced by valine, an amino acid with similar properties. This alteration was detected in a long QT syndrome (LQTS) cohort; however, the patients harbored multiple LQTS alterations and clinical data was not provided (Mullally J et al. Heart Rhythm. 2013;10:378-82). This variant was previously reported in the SNP database (dbSNP) as rs780656919. Based on data from ExAC, the T allele has an overall frequency of less than 0.01% (1/105914). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: No predicted splice impact; 1 paper in HGMD; ExAC: 2/66498 European; ClinVar: 1 VUS
Comment:
This missense variant replaces alanine with valine at codon 715 of the KCNH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study showed that this variant had similar expression compared to wild type (PMID: 26958806). This variant has been reported in individuals affected with long QT syndrome. However, those individuals have other long QT syndrome related co-variants (PMID: 23174487). This variant has been identified in 8/282710 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
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 missense variant replaces alanine with valine at codon 715 of the KCNH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study showed that this variant had similar expression compared to wild type (PMID: 26958806). This variant has been reported in individuals affected with long QT syndrome. However, those individuals have other long QT syndrome related co-variants (PMID: 23174487). This variant has been identified in 8/282710 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
Experimental studies have shown that this missense change does not substantially affect KCNH2 function (PMID: 26958806). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 715 of the KCNH2 protein (p.Ala715Val). This variant is present in population databases (rs780656919, gnomAD 0.01%). This missense change has been observed in individual(s) with long QT syndrome (LQTS) (PMID: 23174487). ClinVar contains an entry for this variant (Variation ID: 200413). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
The p.A715V variant (also known as c.2144C>T), located in coding exon 8 of the KCNH2 gene, results from a C to T substitution at nucleotide position 2144. The alanine at codon 715 is replaced by valine, an amino acid with similar properties. This alteration was detected in a long QT syndrome (LQTS) cohort; however, the patients harbored multiple LQTS alterations and clinical data was not provided (Mullally J et al. Heart Rhythm. 2013;10:378-82). This variant was previously reported in the SNP database (dbSNP) as rs780656919. Based on data from ExAC, the T allele has an overall frequency of less than 0.01% (1/105914). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: No predicted splice impact; 1 paper in HGMD; ExAC: 2/66498 European; ClinVar: 1 VUS
Comment:
This missense variant replaces alanine with valine at codon 715 of the KCNH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study showed that this variant had similar expression compared to wild type (PMID: 26958806). This variant has been reported in individuals affected with long QT syndrome. However, those individuals have other long QT syndrome related co-variants (PMID: 23174487). This variant has been identified in 8/282710 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Rescue of protein expression defects may not be enough to abolish the pro-arrhythmic phenotype of long QT type 2 mutations. | Perry MD | The Journal of physiology | 2016 | PMID: 26958806 |
| Risk of life-threatening cardiac events among patients with long QT syndrome and multiple mutations. | Mullally J | Heart rhythm | 2013 | PMID: 23174487 |
Text-mined citations for rs780656919 ...
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 03, 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.