VCV001120103.16 - ClinVar

NM_000219.6(KCNE1):c.220T>C (p.Ser74Pro)

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.

(5)

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

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.220T>C (p.Ser74Pro)

Variation ID: 1120103 Accession: VCV001120103.16

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 21q22.12 21: 34449415 (GRCh38) [ NCBI UCSC ] 21: 35821713 (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	May 29, 2021	Nov 10, 2024	Apr 30, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000219.6:c.220T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000210.2:p.Ser74Pro	missense
NM_001127668.4:c.220T>C	NP_001121140.1:p.Ser74Pro	missense
NM_001127669.4:c.220T>C	NP_001121141.1:p.Ser74Pro	missense
NM_001127670.4:c.220T>C	NP_001121142.1:p.Ser74Pro	missense
NM_001270402.3:c.220T>C	NP_001257331.1:p.Ser74Pro	missense
NM_001270403.2:c.220T>C	NP_001257332.1:p.Ser74Pro	missense
NM_001270404.3:c.220T>C	NP_001257333.1:p.Ser74Pro	missense
NM_001270405.3:c.220T>C	NP_001257334.1:p.Ser74Pro	missense
NC_000021.9:g.34449415A>G
NC_000021.8:g.35821713A>G
NG_009091.1:g.66901T>C
LRG_290:g.66901T>C
LRG_290t1:c.220T>C

... more HGVS ... less HGVS

Protein change

S74P

Other names

Canonical SPDI

NC_000021.9:34449414:A:G

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 0.334 (0.266-0.401 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 "partial loss of 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.

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

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00002

Links

dbSNP: rs199473357 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	341	419

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 specified	Uncertain significance (1)	criteria provided, single submitter	Jun 10, 2020	RCV001449768.4
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Apr 30, 2024	RCV001509078.8
Long QT syndrome	Uncertain significance (1)	criteria provided, single submitter	Oct 4, 2023	RCV001872003.4
Long QT syndrome 5	not provided (1)	no classification provided	-	RCV004779120.1

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 (Jun 10, 2020)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV001653043.1 First in ClinVar: May 29, 2021 Last updated: May 29, 2021	Comment: The p.Ser74Pro in KCNE1 has not been previously reported in individuals with Jervell and Lange-Nielsen syndrome or long-QT syndrome, but has been identified in 0.01% … (more) The p.Ser74Pro in KCNE1 has not been previously reported in individuals with Jervell and Lange-Nielsen syndrome or long-QT syndrome, but has been identified in 0.01% (5/34592) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). Another variant of uncertain significance p.Ser74Leu has been reported (Splawski 1997 PMID: 9354802, Harmer 2010 PMID: 19907016, LMM Data). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting. (less) Number of individuals with the variant: 1
Uncertain significance (Jul 14, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV001715593.1 First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021	Number of individuals with the variant: 1
Uncertain significance (Oct 04, 2023)	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: SCV002148528.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 9354802‚ 9834138‚ 19008479‚ 19907016‚ 31941373 Comment: This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 74 of the KCNE1 protein (p.Ser74Pro). … (more) This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 74 of the KCNE1 protein (p.Ser74Pro). This variant is present in population databases (rs199473357, gnomAD 0.01%). This missense change has been observed in individuals with long QT syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 1120103). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCNE1 protein function. This variant disrupts the p.Ser74 amino acid residue in KCNE1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9354802, 9834138, 19008479, 19907016, 31941373; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 (Apr 30, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001990052.3 First in ClinVar: Nov 06, 2021 Last updated: Jul 23, 2024	Comment: Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis … (more) Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function (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: SCV005393434.1 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: 0.334 - determined to be "partial loss of function"

Comment:

The p.Ser74Pro in KCNE1 has not been previously reported in individuals with Jervell and Lange-Nielsen syndrome or long-QT syndrome, but has been identified in 0.01% (5/34592) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). Another variant of uncertain significance p.Ser74Leu has been reported (Splawski 1997 PMID: 9354802, Harmer 2010 PMID: 19907016, LMM Data). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting.

Comment:

This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 74 of the KCNE1 protein (p.Ser74Pro). This variant is present in population databases (rs199473357, gnomAD 0.01%). This missense change has been observed in individuals with long QT syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 1120103). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCNE1 protein function. This variant disrupts the p.Ser74 amino acid residue in KCNE1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9354802, 9834138, 19008479, 19907016, 31941373; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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:

Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function

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)	0.334 - determined to be "partial loss of function"	Roden Lab, Vanderbilt University Medical Center Accession: SCV005393434.1	Comment: This variant was studied in a multiplexed assay of variant effect (PMID 38816749). This variant had a mean functional score of 0.334 (0.266-0.401 confidence interval). … (more) This variant was studied in a multiplexed assay of variant effect (PMID 38816749). This variant had a mean functional score of 0.334 (0.266-0.401 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 "partial loss of 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
An International Multicenter Evaluation of Type 5 Long QT Syndrome: A Low Penetrant Primary Arrhythmic Condition.	Roberts JD	Circulation	2020	PMID: 31941373
Mechanisms of disease pathogenesis in long QT syndrome type 5.	Harmer SC	American journal of physiology. Cell physiology	2010	PMID: 19907016
Long QT syndrome-associated mutations in KCNQ1 and KCNE1 subunits disrupt normal endosomal recycling of IKs channels.	Seebohm G	Circulation research	2008	PMID: 19008479
Single-channel characteristics of wild-type IKs channels and channels formed with two minK mutants that cause long QT syndrome.	Sesti F	The Journal of general physiology	1998	PMID: 9834138
Mutations in the hminK gene cause long QT syndrome and suppress IKs function.	Splawski I	Nature genetics	1997	PMID: 9354802

Text-mined citations for rs199473357 ...

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 10, 2024

ClinVar Genomic variation as it relates to human health

NM_000219.6(KCNE1):c.220T>C (p.Ser74Pro)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs199473357 ...