VCV002587504.4 - ClinVar

NM_000219.6(KCNE1):c.246C>G (p.Ile82Met)

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.

(3)

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.246C>G (p.Ile82Met)

Variation ID: 2587504 Accession: VCV002587504.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 21q22.12 21: 34449389 (GRCh38) [ NCBI UCSC ] 21: 35821687 (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	Oct 28, 2023	Nov 10, 2024	Oct 14, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000219.6:c.246C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000210.2:p.Ile82Met	missense
NM_001127668.4:c.246C>G	NP_001121140.1:p.Ile82Met	missense
NM_001127669.4:c.246C>G	NP_001121141.1:p.Ile82Met	missense
NM_001127670.4:c.246C>G	NP_001121142.1:p.Ile82Met	missense
NM_001270402.3:c.246C>G	NP_001257331.1:p.Ile82Met	missense
NM_001270403.2:c.246C>G	NP_001257332.1:p.Ile82Met	missense
NM_001270404.3:c.246C>G	NP_001257333.1:p.Ile82Met	missense
NM_001270405.3:c.246C>G	NP_001257334.1:p.Ile82Met	missense
NC_000021.9:g.34449389G>C
NC_000021.8:g.35821687G>C
NG_009091.1:g.66927C>G
LRG_290:g.66927C>G
LRG_290t1:c.246C>G	LRG_290p1:p.Ile82Met
LRG_290t2:c.246C>G	LRG_290p2:p.Ile82Met

... more HGVS ... less HGVS

Protein change

I82M

Other names

Canonical SPDI

NC_000021.9:34449388:G:C

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 0.385 (0.372-0.398 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.

Links

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.
Long QT syndrome	Uncertain significance (1)	criteria provided, single submitter	Oct 14, 2023	RCV003647982.2
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Aug 1, 2023	RCV003350714.2
Long QT syndrome 5	not provided (1)	no classification provided	-	RCV004780533.1

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 (Oct 14, 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: SCV004547231.1 First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024	Comment: This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 82 of the KCNE1 protein (p.Ile82Met). … (more) This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 82 of the KCNE1 protein (p.Ile82Met). This variant is present in population databases (rs555086287, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with KCNE1-related conditions. 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. 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 (Aug 01, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV004055833.2 First in ClinVar: Oct 28, 2023 Last updated: May 01, 2024	Comment: The p.I82M variant (also known as c.246C>G), located in coding exon 1 of the KCNE1 gene, results from a C to G substitution at nucleotide … (more) The p.I82M variant (also known as c.246C>G), located in coding exon 1 of the KCNE1 gene, results from a C to G substitution at nucleotide position 246. The isoleucine at codon 82 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (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: SCV005393521.1 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: 0.385 - determined to be "partial loss of function"

Comment:

This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 82 of the KCNE1 protein (p.Ile82Met). This variant is present in population databases (rs555086287, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with KCNE1-related conditions. 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. 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:

The p.I82M variant (also known as c.246C>G), located in coding exon 1 of the KCNE1 gene, results from a C to G substitution at nucleotide position 246. The isoleucine at codon 82 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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)	0.385 - determined to be "partial loss of function"	Roden Lab, Vanderbilt University Medical Center Accession: SCV005393521.1	Comment: This variant was studied in a multiplexed assay of variant effect (PMID 38816749). This variant had a mean functional score of 0.385 (0.372-0.398 confidence interval). … (more) This variant was studied in a multiplexed assay of variant effect (PMID 38816749). This variant had a mean functional score of 0.385 (0.372-0.398 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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for this variant ...

Record last updated Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_000219.6(KCNE1):c.246C>G (p.Ile82Met)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...