NM_000219.6(KCNE1):c.23C>T (p.Ala8Val) AND not specified

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 13, 2020
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000455223.5

Allele description [Variation Report for NM_000219.6(KCNE1):c.23C>T (p.Ala8Val)]

NM_000219.6(KCNE1):c.23C>T (p.Ala8Val)

Gene:

KCNE1:potassium voltage-gated channel subfamily E regulatory subunit 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

21q22.12

Genomic location:

Preferred name:

NM_000219.6(KCNE1):c.23C>T (p.Ala8Val)

Other names:

NM_000219.5(KCNE1):c.23C>T(p.Ala8Val); NM_001127668.3(KCNE1):c.23C>T(p.Ala8Val); NM_001127669.3(KCNE1):c.23C>T(p.Ala8Val); NM_001127670.3(KCNE1):c.23C>T(p.Ala8Val); NM_001270402.2(KCNE1):c.23C>T(p.Ala8Val); NM_001270403.2(KCNE1):c.23C>T(p.Ala8Val); NM_001270404.2(KCNE1):c.23C>T(p.Ala8Val); NM_001270405.2(KCNE1):c.23C>T(p.Ala8Val)

HGVS:

NC_000021.9:g.34449612G>A
NG_009091.1:g.66704C>T
NM_000219.6:c.23C>TMANE SELECT
NM_001127668.4:c.23C>T
NM_001127669.4:c.23C>T
NM_001127670.4:c.23C>T
NM_001270402.3:c.23C>T
NM_001270403.2:c.23C>T
NM_001270404.3:c.23C>T
NM_001270405.3:c.23C>T
NP_000210.2:p.Ala8Val
NP_001121140.1:p.Ala8Val
NP_001121141.1:p.Ala8Val
NP_001121142.1:p.Ala8Val
NP_001257331.1:p.Ala8Val
NP_001257332.1:p.Ala8Val
NP_001257333.1:p.Ala8Val
NP_001257334.1:p.Ala8Val
LRG_290t1:c.23C>T
LRG_290:g.66704C>T
NC_000021.8:g.35821910G>A
NM_000219.3:c.23C>T
NM_000219.4:c.23C>T
NM_000219.5:c.23C>T
NM_001127670.4:c.23C>T
P15382:p.Ala8Val

Protein change:

A8V

Links:

UniProtKB: P15382#VAR_074908; dbSNP: rs199473348

NCBI 1000 Genomes Browser:

rs199473348

Molecular consequence:

NM_000219.6:c.23C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127668.4:c.23C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127669.4:c.23C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127670.4:c.23C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001270402.3:c.23C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001270403.2:c.23C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001270404.3:c.23C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001270405.3:c.23C>T - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

Effect on ion channel function [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0001] - Comment(s)

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000539419	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Aug 9, 2018)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 19716085, 25650408, 24400172, 18776039, 17341399, 24033266
SCV001337808	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Jan 13, 2020)	germline	clinical testing	PubMed (17) [See all records that cite these PMIDs] 19716085, 19695459, 17341399, 25650408, 19862833, 26715165, 24400172, 26410412, 28767663, 31535183, 26926294, 30461122, 20541041, 28988457, 31521807, 18776039, 30123799 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000539419

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Aug 9, 2018)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV001337808

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Jan 13, 2020)

germline

clinical testing

PubMed (17)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	1	1	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test.

Kapplinger JD, Tester DJ, Salisbury BA, Carr JL, Harris-Kerr C, Pollevick GD, Wilde AA, Ackerman MJ.

Heart Rhythm. 2009 Sep;6(9):1297-303. doi: 10.1016/j.hrthm.2009.05.021. Epub 2009 Jun 23.

PubMed [citation]

PMID:: 19716085
PMCID:: PMC3049907

See all PubMed Citations (18)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000539419.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (6)

Description

The p.Ala8Val variant in KCNE1 has been reported in the heterozygous state in on e individual with paroxysmal atrial fibrillation and sick sinus syndrome and one individual with Long QT syndrome (Ohno 2007, Sale 2008, Kapplinger 2009). This variant has been identified in 11/18860 East Asian chromosomes by the Genome Agg regation Database (gnomAD, http://gnomad.broadinstitute.org/) and is reported in ClinVar (Variation ID: 132670). In vitro functional studies provide some eviden ce that the p.Ala8Val variant may impact protein function (Ohno 2007, Sale 2008, Du 2013). However, these types of assays may not accurately represent biologica l function. Alanine (Ala) at position 8 is not conserved in mammals or evolution arily distant species and 4 mammals carry a Valine (Val) at this position, raisi ng the possibility that this change may be tolerated. Additional computational p rediction tools suggest that the p.Ala8Val variant may not impact the protein, t hough this information is not predictive enough to rule out pathogenicity. In su mmary, the clinical significance of the p.Ala8Val variant is uncertain. ACMG/AMP Criteria applied: PS3_Supporting, PS4_Supporting, BP4_Strong.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		1	not provided	1	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001337808.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (17)

Description

Variant summary: KCNE1 c.23C>T (p.Ala8Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 251512 control chromosomes. The observed variant frequency is approximately 10.7- fold the estimated maximal expected allele frequency for a pathogenic variant in KCNE1 causing Arrhythmia phenotype (1e-05), suggesting that the variant is benign. However, c.23C>T has been reported in the literature in multiple individuals affected with arrhythmia (e.g. Ohno_2007, Sale_2008, Kapplinger_2009, Fedida_2017, Bennett_2019, Li_2019), including three individuals from one family in which the variant segregated with a Long QT Syndrome (LQTS) phenotype (Li_2019). These data indicate that the variant may be associated with disease. At least three publications report experimental evidence evaluating the electrophysiological effects of the variant on potassium channels and suggest that the variant may alter channel kinetics, however the biological consequences fo these findings are not clear (e.g. Ohno_2007, Sale, 2008, Du_2013). Four other ClinVar submitters (evaluation after 2014) have cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 10, 2024

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