ClinVar Genomic variation as it relates to human health
NM_172201.2(KCNE2):c.229C>T (p.Arg77Trp)
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.
Uncertain significance(5); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_172201.2(KCNE2):c.229C>T (p.Arg77Trp)
Variation ID: 67614 Accession: VCV000067614.12
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 21q22.11 21: 34370707 (GRCh38) [ NCBI UCSC ] 21: 35743006 (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 Dec 6, 2014 Feb 7, 2023 Oct 27, 2022 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_172201.2:c.229C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_751951.1:p.Arg77Trp missense NC_000021.9:g.34370707C>T NC_000021.8:g.35743006C>T NG_008804.1:g.11684C>T LRG_291:g.11684C>T LRG_291t1:c.229C>T LRG_291p1:p.Arg77Trp Q9Y6J6:p.Arg77Trp - Protein change
- R77W
- Other names
- p.R77W:CGG>TGG
- Canonical SPDI
- NC_000021.9:34370706: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.
The Genome Aggregation Database (gnomAD) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00009
The Genome Aggregation Database (gnomAD), exomes 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00006
Exome Aggregation Consortium (ExAC) 0.00007
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
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. |
|||
KCNE2 | - | - |
GRCh38 GRCh37 |
1 | 217 | |
LOC105372791 | - | - | - | GRCh38 | - | 168 |
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. |
---|---|---|---|---|
not provided (1) |
no classification provided
|
- | RCV000058367.5 | |
Uncertain significance (1) |
no assertion criteria provided
|
Jun 1, 2014 | RCV000148522.4 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Jun 14, 2020 | RCV000170957.9 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Sep 4, 2018 | RCV000781484.3 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Oct 27, 2022 | RCV001246221.6 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Oct 2, 2021 | RCV002477193.3 | |
Likely benign (1) |
criteria provided, single submitter
|
Oct 17, 2022 | RCV002444517.3 |
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. |
|
---|---|---|---|---|---|
Uncertain significance
(Sep 04, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000919551.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: KCNE2 c.229C>T (p.Arg77Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: KCNE2 c.229C>T (p.Arg77Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.7e-05 in 246246 control chromosomes. The observed variant frequency is approximately 1.1 fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNE2 causing Arrhythmia phenotype (7e-05), suggesting that the variant may be benign. c.229C>T has been reported in the literature in individuals affected with LQTS, Brugada syndrome and sudden death (Chevalier_2007, Di Resta_2015, Methner_2016, Millat_2006), without strong evidence for causality. These report(s) do not provide unequivocal conclusions about association of the variant with Arrhythmia. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as a VUS. (less)
|
|
Uncertain significance
(Jun 15, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000223519.14
First in ClinVar: May 23, 2015 Last updated: Apr 17, 2019 |
Comment:
The R77W variant in the KCNE2 gene has been reported in patients with prolonged QT intervals (Millat et al., 2006; Chevalier et al., 2007) and … (more)
The R77W variant in the KCNE2 gene has been reported in patients with prolonged QT intervals (Millat et al., 2006; Chevalier et al., 2007) and in a patient with aborted cardiac arrest (Roberts et al., 2017). Initially, Millat et al. (2006) reported R77W in one individual with a prolonged QTc interval of 514 ms, syncope, and bradycardia. Subsequently, Chevalier et al. (2007) reported R77W in one individual with a prolonged QTc interval of >600 ms and atrioventricular block. In addition, this variant has also been identified independently in multiple unrelated individuals referred for LQTS genetic testing at GeneDx; however, thus far, segregation data is limited or absent for these individuals due to the lack of clinical information provided and/or insufficient participation by informative family members. Moreover, functional studies indicate that R77W does not impact potassium channel current (Chevalier et al., 2007). The R77W variant is observed in 19/246246 (0.008%) alleles from individuals of multiple ethnic backgrounds in large population cohorts (Lek et al., 2016). Nonetheless, the R77W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Finally, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign. (less)
|
|
Uncertain significance
(Jun 14, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002503391.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
|
|
Likely benign
(Oct 17, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002733972.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, … (more)
This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Number of individuals with the variant: 1
|
|
Uncertain significance
(Oct 02, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Atrial fibrillation, familial, 4
Long QT syndrome 6
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002793803.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
Uncertain significance
(Oct 27, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Long QT syndrome 6
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV001419562.4
First in ClinVar: Jul 16, 2020 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 77 of the KCNE2 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 77 of the KCNE2 protein (p.Arg77Trp). This variant is present in population databases (rs141423405, gnomAD 0.01%). This missense change has been observed in individual(s) with or evaluated for long QT syndrome, arrhythmia, or Brugada syndrome (PMID: 16922724, 17275752, 26220970, 28794082). ClinVar contains an entry for this variant (Variation ID: 67614). 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 C15"). Experimental studies have shown that this missense change does not substantially affect KCNE2 function (PMID: 17275752). 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)
|
|
Uncertain significance
(Jun 01, 2014)
|
no assertion criteria provided
Method: research
|
Long QT syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190234.1 First in ClinVar: Dec 06, 2014 Last updated: Dec 06, 2014 |
|
|
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: SCV000089887.3
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:16922724;PMID:17275752;PMID:22378279). 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:16922724;PMID:17275752;PMID:22378279). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. (less)
|
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 |
---|---|---|---|---|
Reclassification of Variants of Uncertain Significance in Children with Inherited Arrhythmia Syndromes is Predicted by Clinical Factors. | Bennett JS | Pediatric cardiology | 2019 | PMID: 31535183 |
HCN ion channels and accessory proteins in epilepsy: genetic analysis of a large cohort of patients and review of the literature. | DiFrancesco JC | Epilepsy research | 2019 | PMID: 30986657 |
Loss-of-Function KCNE2 Variants: True Monogenic Culprits of Long-QT Syndrome or Proarrhythmic Variants Requiring Secondary Provocation? | Roberts JD | Circulation. Arrhythmia and electrophysiology | 2017 | PMID: 28794082 |
Postmortem genetic screening for the identification, verification, and reporting of genetic variants contributing to the sudden death of the young. | Methner DN | Genome research | 2016 | PMID: 27435932 |
High-throughput genetic characterization of a cohort of Brugada syndrome patients. | Di Resta C | Human molecular genetics | 2015 | PMID: 26220970 |
Actionable exomic incidental findings in 6503 participants: challenges of variant classification. | Amendola LM | Genome research | 2015 | PMID: 25637381 |
High prevalence of genetic variants previously associated with LQT syndrome in new exome data. | Refsgaard L | European journal of human genetics : EJHG | 2012 | PMID: 22378279 |
Torsades de pointes complicating atrioventricular block: evidence for a genetic predisposition. | Chevalier P | Heart rhythm | 2007 | PMID: 17275752 |
Spectrum of pathogenic mutations and associated polymorphisms in a cohort of 44 unrelated patients with long QT syndrome. | Millat G | Clinical genetics | 2006 | PMID: 16922724 |
Text-mined citations for rs141423405 ...
HelpRecord last updated Oct 15, 2023
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.