ClinVar Genomic variation as it relates to human health
NM_000238.4(KCNH2):c.1319C>T (p.Pro440Leu)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000238.4(KCNH2):c.1319C>T (p.Pro440Leu)
Variation ID: 67185 Accession: VCV000067185.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q36.1 7: 150952663 (GRCh38) [ NCBI UCSC ] 7: 150649751 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 9, 2016 Apr 20, 2024 Nov 13, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000238.4:c.1319C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000229.1:p.Pro440Leu missense NM_001204798.2:c.299C>T NP_001191727.1:p.Pro100Leu missense NM_001406753.1:c.1031C>T NP_001393682.1:p.Pro344Leu missense NM_001406755.1:c.1142C>T NP_001393684.1:p.Pro381Leu missense NM_001406756.1:c.1031C>T NP_001393685.1:p.Pro344Leu missense NM_001406757.1:c.1019C>T NP_001393686.1:p.Pro340Leu missense NM_172056.3:c.1319C>T NP_742053.1:p.Pro440Leu missense NM_172057.3:c.299C>T NP_742054.1:p.Pro100Leu missense NR_176254.1:n.1727C>T NR_176255.1:n.600C>T NC_000007.14:g.150952663G>A NC_000007.13:g.150649751G>A NG_008916.1:g.30264C>T LRG_288:g.30264C>T LRG_288t1:c.1319C>T LRG_288p1:p.Pro440Leu LRG_288t2:c.1319C>T LRG_288p2:p.Pro440Leu LRG_288t3:c.299C>T LRG_288p3:p.Pro100Leu Q12809:p.Pro440Leu - Protein change
- P100L, P440L, P340L, P381L, P344L
- Other names
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- Canonical SPDI
- NC_000007.14:150952662: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
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
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 | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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. |
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KCNH2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3219 | 3305 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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not provided (1) |
no classification provided
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- | RCV000057892.11 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Mar 29, 2022 | RCV001531068.17 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 9, 2023 | RCV001841697.11 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Nov 13, 2023 | RCV001854191.15 |
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
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Mar 29, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics
Accession: SCV002771571.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Mar 12, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001779701.1
First in ClinVar: Aug 11, 2021 Last updated: Aug 11, 2021 |
Comment:
Identified in patients with suspected long QT syndrome or sudden cardiac death, but there is conflicting determination of its pathogenicity (Kapplinger et al., 2009; Quenin … (more)
Identified in patients with suspected long QT syndrome or sudden cardiac death, but there is conflicting determination of its pathogenicity (Kapplinger et al., 2009; Quenin et al., 2017; Mattivi et al., 2019); Not observed at a significant frequency in large population cohorts, and no individuals were reported to be homozygous (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28912206, 19716085, 31493592) (less)
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Uncertain significance
(Nov 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002123662.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 440 of the KCNH2 protein (p.Pro440Leu). … (more)
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 440 of the KCNH2 protein (p.Pro440Leu). This variant is present in population databases (rs199473509, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of KCNH2-related conditions (PMID: 19716085, 28912206). ClinVar contains an entry for this variant (Variation ID: 67185). 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 tolerated. 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
(Feb 09, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiac arrhythmia
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV001348921.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces proline with leucine at codon 440 of the KCNH2 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces proline with leucine at codon 440 of the KCNH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with long QT syndrome (PMID:19716085). This variant has been identified in 4/251474 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
(Aug 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004844009.1
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)
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Comment:
This missense variant replaces proline with leucine at codon 440 of the KCNH2 protein. Computational prediction tool is inconclusive regarding the impact of this variant … (more)
This missense variant replaces proline with leucine at codon 440 of the KCNH2 protein. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with long QT syndrome (PMID:19716085). This variant has been identified in 4/251474 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: 7
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not provided
(-)
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no classification provided
Method: literature only
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Congenital long QT syndrome
Affected status: unknown
Allele origin:
germline
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Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust
Accession: SCV000089412.3
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:19716085). This is a literature report, and does not necessarily … (more)
This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Utilization of the genome aggregation database, in silico tools, and heterologous expression patch-clamp studies to identify and demote previously published type 2 long QT syndrome: Causative variants from pathogenic to likely benign. | Mattivi CL | Heart rhythm | 2020 | PMID: 31493592 |
Clinical Yield of Familial Screening After Sudden Death in Young Subjects: The French Experience. | Quenin P | Circulation. Arrhythmia and electrophysiology | 2017 | PMID: 28912206 |
Paralogous annotation of disease-causing variants in long QT syndrome genes. | Ware JS | Human mutation | 2012 | PMID: 22581653 |
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 |
Text-mined citations for rs199473509 ...
HelpRecord last updated Oct 13, 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.