VCV000178611.59 - ClinVar

NM_000219.6(KCNE1):c.84G>A (p.Ser28=)

Germline

Classification

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.

(17)

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.

Benign/Likely benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000219.6(KCNE1):c.84G>A (p.Ser28=)

Variation ID: 178611 Accession: VCV000178611.59

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 21q22.12 21: 34449551 (GRCh38) [ NCBI UCSC ] 21: 35821849 (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, 2016	Nov 10, 2024	Jan 30, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000219.6:c.84G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000210.2:p.Ser28=	synonymous
NM_001127668.4:c.84G>A	NP_001121140.1:p.Ser28=	synonymous
NM_001127669.4:c.84G>A	NP_001121141.1:p.Ser28=	synonymous
NM_001127670.4:c.84G>A	NP_001121142.1:p.Ser28=	synonymous
NM_001270402.3:c.84G>A	NP_001257331.1:p.Ser28=	synonymous
NM_001270403.2:c.84G>A	NP_001257332.1:p.Ser28=	synonymous
NM_001270404.3:c.84G>A	NP_001257333.1:p.Ser28=	synonymous
NM_001270405.3:c.84G>A	NP_001257334.1:p.Ser28=	synonymous
NC_000021.9:g.34449551C>T
NC_000021.8:g.35821849C>T
NG_009091.1:g.66765G>A
LRG_290:g.66765G>A
LRG_290t1:c.84G>A

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000021.9:34449550:C:T

Functional consequence Help The 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 0.980 (0.667-1.294 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) Help The 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.

0.00379 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00362

1000 Genomes Project 0.00379

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00415

The Genome Aggregation Database (gnomAD) 0.00676

Links

ClinGen: CA182655 dbSNP: rs17173510 VarSome

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
Gene	OMIM	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.
Long QT syndrome	Benign (1)	criteria provided, single submitter	Jan 30, 2024	RCV000228309.22
not specified	Benign (4)	criteria provided, multiple submitters, no conflicts	Jul 17, 2015	RCV000155364.19
Cardiovascular phenotype	Benign (1)	criteria provided, single submitter	Apr 11, 2016	RCV000248775.12
Jervell and Lange-Nielsen syndrome 2	Likely benign (1)	criteria provided, single submitter	Apr 27, 2017	RCV000393664.13
not provided	Benign/Likely benign (7)	criteria provided, multiple submitters, no conflicts	Oct 6, 2023	RCV000589403.39
Long QT syndrome 5	Likely benign (2)	criteria provided, single submitter	Apr 27, 2017	RCV001094635.13
Jervell and Lange-Nielsen syndrome 2 Long QT syndrome 5	Benign (1)	criteria provided, single submitter	Feb 17, 2022	RCV002498753.8

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.
Benign (Jul 17, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000332686.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=KCNE1 Number of individuals with the variant: 1 Zygosity: Single Heterozygote Sex: mixed
Benign (Oct 06, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001477537.2 First in ClinVar: Jan 26, 2021 Last updated: Feb 20, 2024
Benign (Aug 09, 2016)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000695997.1 First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018	Publications: PubMed (2) PubMed: 16887036‚ 18752142 Comment: Variant summary: The KCNE1 c.84G>A (p.Ser28Ser) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a … (more) Variant summary: The KCNE1 c.84G>A (p.Ser28Ser) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a benign outcome for this variant. This variant was found in 438/120954 control chromosomes at a frequency of 0.0036212, which is approximately 362 times the estimated maximal expected allele frequency of a pathogenic KCNE1 variant (0.00001), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign and multiple publications have classified the variant as "normal/polymorphism". Taken together, this variant is classified as benign. (less)
Benign (May 07, 2012)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000205051.4 First in ClinVar: Jan 31, 2015 Last updated: Dec 06, 2016	Comment: "Ser28Ser in Exon 03 of KCNE1: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, … (more) "Ser28Ser in Exon 03 of KCNE1: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 0.6% (40/7020) of Eur opean American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs17173510)." (less) Number of individuals with the variant: 15
Benign (Mar 03, 2015)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001886886.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021
Benign (Feb 17, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Jervell and Lange-Nielsen syndrome 2 Long QT syndrome 5 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002809436.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Benign (Jan 30, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Long QT syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000283891.10 First in ClinVar: Jul 01, 2016 Last updated: Feb 20, 2024
Benign (Apr 11, 2016)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000318604.7 First in ClinVar: Oct 02, 2016 Last updated: May 01, 2024	Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as 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)
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005206237.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Likely benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Long QT syndrome 5 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000435791.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Likely benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Jervell and Lange-Nielsen syndrome 2 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000435792.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Likely benign (Jul 01, 2022)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001153554.26 First in ClinVar: Feb 03, 2020 Last updated: Oct 20, 2024	Comment: ENSG00000276289: BP4, BP7; KCNE1: BP4, BP7 Number of individuals with the variant: 1
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001954224.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001922332.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001928212.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001975785.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
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: SCV005392989.1 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: 0.980 - determined to be "normal function"
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Comment:

Variant summary: The KCNE1 c.84G>A (p.Ser28Ser) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a benign outcome for this variant. This variant was found in 438/120954 control chromosomes at a frequency of 0.0036212, which is approximately 362 times the estimated maximal expected allele frequency of a pathogenic KCNE1 variant (0.00001), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign and multiple publications have classified the variant as "normal/polymorphism". Taken together, this variant is classified as benign.

Comment:

"Ser28Ser in Exon 03 of KCNE1: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 0.6% (40/7020) of Eur opean American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs17173510)."

Comment:

This alteration is classified as 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:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

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 (FENICS-0001)	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. Method citation(s): PubMed(1)	0.980 - determined to be "normal function"	Roden Lab, Vanderbilt University Medical Center Accession: SCV005392989.1	Comment: This variant was studied in a multiplexed assay of variant effect (PMID 38816749). This variant had a mean functional score of 0.980 (0.667-1.294 confidence interval). … (more) This variant was studied in a multiplexed assay of variant effect (PMID 38816749). This variant had a mean functional score of 0.980 (0.667-1.294 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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Molecular genetic analysis of long QT syndrome in Norway indicating a high prevalence of heterozygous mutation carriers.	Berge KE	Scandinavian journal of clinical and laboratory investigation	2008	PMID: 18752142
Potassium channel gene mutations rarely cause atrial fibrillation.	Ellinor PT	BMC medical genetics	2006	PMID: 16887036
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=KCNE1	-	-	-	-

Text-mined citations for rs17173510 ...

These 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 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000219.6(KCNE1):c.84G>A (p.Ser28=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs17173510 ...