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: This variant is present in 5 papers in HGMD but comments suggest not pathogenic. 32 mammals have an Ile at this position. The variant is classified in ClinVar with 1 star as VUS by CSER_CC_NCGL and Royal Brompton & Harefield NHS Foundation Trust. The variant is present at 0.07% in gnomAD (18 African chrs).
ClinVar Genomic variation as it relates to human health
NM_000219.6(KCNE1):c.325G>A (p.Val109Ile)
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.
(10)
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.
Conflicting classifications of pathogenicity
Uncertain significance(5); Likely benign(3)
Uncertain significance(5); Likely benign(3)
10
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000219.6(KCNE1):c.325G>A (p.Val109Ile)
Variation ID: 132678 Accession: VCV000132678.20
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 21q22.12 21: 34449310 (GRCh38) [ NCBI UCSC ] 21: 35821608 (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 Nov 10, 2024 Jul 29, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000219.6:c.325G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000210.2:p.Val109Ile missense NM_001127668.4:c.325G>A NP_001121140.1:p.Val109Ile missense NM_001127669.4:c.325G>A NP_001121141.1:p.Val109Ile missense NM_001127670.4:c.325G>A NP_001121142.1:p.Val109Ile missense NM_001270402.3:c.325G>A NP_001257331.1:p.Val109Ile missense NM_001270403.2:c.325G>A NP_001257332.1:p.Val109Ile missense NM_001270404.3:c.325G>A NP_001257333.1:p.Val109Ile missense NM_001270405.3:c.325G>A NP_001257334.1:p.Val109Ile missense NC_000021.9:g.34449310C>T NC_000021.8:g.35821608C>T NG_009091.1:g.67006G>A LRG_290:g.67006G>A LRG_290t1:c.325G>A P15382:p.Val109Ile - Protein change
- V109I
- Other names
- -
- Canonical SPDI
- NC_000021.9:34449309:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
Effect on ion channel function; Functional Epilepsy Nomenclature for Ion Channels [ FENICS-0001]This variant was studied in a multiplexed assay of variant effect (PMID 38816749). This variant had a mean functional score of 1.212 (1.016-1.407 confidence interval). This score is on a scale where the median nonsense variant had a score of 0 and the median synonymous variant had a score of 1. This score was determined to be "normal function". Calibration with control variants resulted in a recommended application of PS3 or BS3 at a maximum of moderate level for this assay. [submitted by Roden Lab, Vanderbilt University Medical Center]
-
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), exomes 0.00013
The Genome Aggregation Database (gnomAD) 0.00014
Exome Aggregation Consortium (ExAC) 0.00015
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
Trans-Omics for Precision Medicine (TOPMed) 0.00020
- 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. |
|||
| KCNE1 | - | - |
GRCh38 GRCh37 |
1261 | 1339 | |
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. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Dec 30, 2023 | RCV000148514.11 | |
| Uncertain significance (2) |
criteria provided, single submitter
|
Oct 6, 2023 | RCV000119090.8 | |
| Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Jul 29, 2024 | RCV000455774.8 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Sep 8, 2021 | RCV002498541.1 | |
| Uncertain significance (2) |
criteria provided, single submitter
|
Mar 20, 2018 | RCV000678944.3 | |
| Likely benign (1) |
criteria provided, single submitter
|
Feb 11, 2020 | RCV002444575.2 |
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
(Jan 24, 2017)
|
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: SCV000539417.1
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: This variant is present in 5 papers in HGMD but comments suggest not pathogenic. 32 mammals have an Ile at this position. The variant is classified in ClinVar with 1 star as VUS by CSER_CC_NCGL and Royal Brompton & Harefield NHS Foundation Trust. The variant is present at 0.07% in gnomAD (18 African chrs). (less)
Method: Genome/Exome Filtration
|
|
|
Uncertain significance
(Sep 08, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Jervell and Lange-Nielsen syndrome 2
Long QT syndrome 5
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002775551.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Likely benign
(Dec 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Long QT syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000627408.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
|
|
|
Likely benign
(Feb 11, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002611423.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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)
|
|
|
Uncertain significance
(Jun 01, 2014)
|
criteria provided, single submitter
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: SCV000190226.2 First in ClinVar: Dec 06, 2014 Last updated: Dec 06, 2014
Comment:
Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
|
Comment:
Low GERP score may suggest that this variant may belong in a lower pathogenicity class
|
|
|
Likely benign
(Jul 29, 2024)
|
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: SCV000919548.3
First in ClinVar: Jun 02, 2019 Last updated: Sep 16, 2024 |
Comment:
Variant summary: KCNE1 c.325G>A (p.Val109Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign … (more)
Variant summary: KCNE1 c.325G>A (p.Val109Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 251204 control chromosomes. The observed variant frequency is approximately 13 fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNE1 causing Arrhythmia phenotype (1e-05). c.325G>A, has been reported in the literature in individuals affected with features of Long QT Syndrome (LQTS/Arrhythmia) without strong evidence for causality, including lack of segregation in an index patient and his asymptomatic father who both carry the variant (example, Schulze-Bahr_2001, Ghouse_2015, Ohno_2007, Mahdieh_2020). These data do not allow any conclusion about variant significance. At least two publications report experimental evidence evaluating an impact on protein function with conflicting results (Dvir_2014; Schulze-Bahr_2001). The following publications have been ascertained in the context of this evaluation (PMID: 22378279, 17341399, 26410412, 25037568, 11692163, 26159999, 32470535). ClinVar contains an entry for this variant (Variation ID: 132678). Based on the evidence outlined above, the variant was classified as likely benign. (less)
|
|
|
Uncertain significance
(Mar 20, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Long QT syndrome 5
Affected status: yes
Allele origin:
unknown
|
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues
Accession: SCV000805157.1
First in ClinVar: Sep 14, 2018 Last updated: Sep 14, 2018 |
|
|
|
Uncertain significance
(Oct 06, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000779612.5
First in ClinVar: Oct 09, 2016 Last updated: Nov 25, 2023 |
Comment:
Reported in association with LQTS (Schulze-Bahr et al., 2001); however, this variant has also been reported in control populations and in at least one individual … (more)
Reported in association with LQTS (Schulze-Bahr et al., 2001); however, this variant has also been reported in control populations and in at least one individual with a normal QT interval (Ackerman et al., 2003; Ghouse et al., 2015); Two functional studies have conflicting results regarding the effect of this variant on channel function (Schulze-Bahr et al., 2001; Dvir et al., 2014); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24710009, 22378279, 25637381, 26159999, 14661677, 11692163, 34426522, 31043699, 32470535, 28988457, 30461122, 31941373, 25037568) (less)
|
|
|
not provided
(-)
|
no classification provided
Method: in vitro
|
Long QT syndrome 5
Affected status: not applicable
Allele origin:
not applicable
|
Roden Lab, Vanderbilt University Medical Center
Accession: SCV005393771.1
First in ClinVar: Nov 10, 2024 Last updated: Nov 10, 2024 |
Comment on evidence:
Functional evidence assertions were derived from functional fitness scores.
Method: Functional assay results from a multiplexed deep mutational scan of KCNE1, measuring cell fitness with Illumina sequencing (a proxy for potassium channel function). Variant outcomes derived from functional score categorization using predefined thresholds and OddsPath assay to determine strength of functional evidence for ACMG/AMP functional assay criteria.
Result:
1.212 - determined to be "normal function"
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
not provided
Affected status: unknown
Allele origin:
germline
|
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust
Accession: SCV000153809.2
First in ClinVar: Jun 03, 2014 Last updated: Oct 09, 2016 |
Comment:
This variant has been reported in the following publications (PMID:11692163;PMID:14661677;PMID:22378279).
|
Comment:
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Comment:
Low GERP score may suggest that this variant may belong in a lower pathogenicity class
Comment:
Variant summary: KCNE1 c.325G>A (p.Val109Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 251204 control chromosomes. The observed variant frequency is approximately 13 fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNE1 causing Arrhythmia phenotype (1e-05). c.325G>A, has been reported in the literature in individuals affected with features of Long QT Syndrome (LQTS/Arrhythmia) without strong evidence for causality, including lack of segregation in an index patient and his asymptomatic father who both carry the variant (example, Schulze-Bahr_2001, Ghouse_2015, Ohno_2007, Mahdieh_2020). These data do not allow any conclusion about variant significance. At least two publications report experimental evidence evaluating an impact on protein function with conflicting results (Dvir_2014; Schulze-Bahr_2001). The following publications have been ascertained in the context of this evaluation (PMID: 22378279, 17341399, 26410412, 25037568, 11692163, 26159999, 32470535). ClinVar contains an entry for this variant (Variation ID: 132678). Based on the evidence outlined above, the variant was classified as likely benign.
Comment:
Reported in association with LQTS (Schulze-Bahr et al., 2001); however, this variant has also been reported in control populations and in at least one individual with a normal QT interval (Ackerman et al., 2003; Ghouse et al., 2015); Two functional studies have conflicting results regarding the effect of this variant on channel function (Schulze-Bahr et al., 2001; Dvir et al., 2014); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24710009, 22378279, 25637381, 26159999, 14661677, 11692163, 34426522, 31043699, 32470535, 28988457, 30461122, 31941373, 25037568)
Comment:
This variant has been reported in the following publications (PMID:11692163;PMID:14661677;PMID:22378279).
Germline Functional Evidence
| Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|---|---|---|---|
|
Effect on ion channel function
|
Method citation(s):
|
|
Roden Lab, Vanderbilt University Medical Center
Accession: SCV005393771.1
|
Comment:
This variant was studied in a multiplexed assay of variant effect (PMID 38816749). This variant had a mean functional score of 1.212 (1.016-1.407 confidence interval). … (more)
This variant was studied in a multiplexed assay of variant effect (PMID 38816749). This variant had a mean functional score of 1.212 (1.016-1.407 confidence interval). This score is on a scale where the median nonsense variant had a score of 0 and the median synonymous variant had a score of 1. This score was determined to be "normal function". Calibration with control variants resulted in a recommended application of PS3 or BS3 at a maximum of moderate level for this assay. (less)
|
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: This variant is present in 5 papers in HGMD but comments suggest not pathogenic. 32 mammals have an Ile at this position. The variant is classified in ClinVar with 1 star as VUS by CSER_CC_NCGL and Royal Brompton & Harefield NHS Foundation Trust. The variant is present at 0.07% in gnomAD (18 African chrs).
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Comment:
Low GERP score may suggest that this variant may belong in a lower pathogenicity class
Comment:
Variant summary: KCNE1 c.325G>A (p.Val109Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 251204 control chromosomes. The observed variant frequency is approximately 13 fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNE1 causing Arrhythmia phenotype (1e-05). c.325G>A, has been reported in the literature in individuals affected with features of Long QT Syndrome (LQTS/Arrhythmia) without strong evidence for causality, including lack of segregation in an index patient and his asymptomatic father who both carry the variant (example, Schulze-Bahr_2001, Ghouse_2015, Ohno_2007, Mahdieh_2020). These data do not allow any conclusion about variant significance. At least two publications report experimental evidence evaluating an impact on protein function with conflicting results (Dvir_2014; Schulze-Bahr_2001). The following publications have been ascertained in the context of this evaluation (PMID: 22378279, 17341399, 26410412, 25037568, 11692163, 26159999, 32470535). ClinVar contains an entry for this variant (Variation ID: 132678). Based on the evidence outlined above, the variant was classified as likely benign.
Comment:
Reported in association with LQTS (Schulze-Bahr et al., 2001); however, this variant has also been reported in control populations and in at least one individual with a normal QT interval (Ackerman et al., 2003; Ghouse et al., 2015); Two functional studies have conflicting results regarding the effect of this variant on channel function (Schulze-Bahr et al., 2001; Dvir et al., 2014); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24710009, 22378279, 25637381, 26159999, 14661677, 11692163, 34426522, 31043699, 32470535, 28988457, 30461122, 31941373, 25037568)
Comment:
This variant has been reported in the following publications (PMID:11692163;PMID:14661677;PMID:22378279).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genetic homozygosity in a diverse population: An experience of long QT syndrome. | Mahdieh N | International journal of cardiology | 2020 | PMID: 32470535 |
| An International Multicenter Evaluation of Type 5 Long QT Syndrome: A Low Penetrant Primary Arrhythmic Condition. | Roberts JD | Circulation | 2020 | PMID: 31941373 |
| Reappraisal of variants previously linked with sudden infant death syndrome: results from three population-based cohorts. | Paludan-Müller C | European journal of human genetics : EJHG | 2019 | PMID: 31043699 |
| Re-evaluating pathogenicity of variants associated with the long QT syndrome. | Kaltman JR | Journal of cardiovascular electrophysiology | 2018 | PMID: 28988457 |
| KCNE1 and KCNE3: The yin and yang of voltage-gated K(+) channel regulation. | Abbott GW | Gene | 2016 | PMID: 26410412 |
| Rare genetic variants previously associated with congenital forms of long QT syndrome have little or no effect on the QT interval. | Ghouse J | European heart journal | 2015 | PMID: 26159999 |
| Actionable exomic incidental findings in 6503 participants: challenges of variant classification. | Amendola LM | Genome research | 2015 | PMID: 25637381 |
| Long QT mutations at the interface between KCNQ1 helix C and KCNE1 disrupt I(KS) regulation by PKA and PIP₂. | Dvir M | Journal of cell science | 2014 | PMID: 25037568 |
| 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 |
| An Examination of KCNE1 Mutations and Common Variants in Chronic Tinnitus. | Sand PG | Genes | 2010 | PMID: 24710009 |
| N- and C-terminal KCNE1 mutations cause distinct phenotypes of long QT syndrome. | Ohno S | Heart rhythm | 2007 | PMID: 17341399 |
| Ethnic differences in cardiac potassium channel variants: implications for genetic susceptibility to sudden cardiac death and genetic testing for congenital long QT syndrome. | Ackerman MJ | Mayo Clinic proceedings | 2003 | PMID: 14661677 |
| A novel long-QT 5 gene mutation in the C-terminus (V109I) is associated with a mild phenotype. | Schulze-Bahr E | Journal of molecular medicine (Berlin, Germany) | 2001 | PMID: 11692163 |
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Text-mined citations for rs77442996 ...
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.