NM_000219.6(KCNE1):c.23C>T (p.Ala8Val) AND Long QT syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 16, 2024
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:: RCV000148516.8

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)

Condition(s)

Name:: Long QT syndrome (LQTS)
Identifiers:: MONDO: MONDO:0002442; MeSH: D008133; MedGen: C0023976

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000190228	CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation	criteria provided, single submitter (Amendola et al. (Genome Res. 2015))	Uncertain significance (Jun 1, 2014)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV000549149	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 16, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 19716085, 31521807, 31535183, 34403091, 17341399, 18776039, 24400172, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000190228

CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation

criteria provided, single submitter

(Amendola et al. (Genome Res. 2015))

Uncertain significance
(Jun 1, 2014)

germline

research

PubMed (1)
[See all records that cite this PMID]

SCV000549149

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 16, 2024)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Actionable exomic incidental findings in 6503 participants: challenges of variant classification.

Amendola LM, Dorschner MO, Robertson PD, Salama JS, Hart R, Shirts BH, Murray ML, Tokita MJ, Gallego CJ, Kim DS, Bennett JT, Crosslin DR, Ranchalis J, Jones KL, Rosenthal EA, Jarvik ER, Itsara A, Turner EH, Herman DS, Schleit J, Burt A, Jamal SM, et al.

Genome Res. 2015 Mar;25(3):305-15. doi: 10.1101/gr.183483.114. Epub 2015 Jan 30.

PubMed [citation]

PMID:: 25637381
PMCID:: PMC4352885

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 (9)

Details of each submission

From CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation, SCV000190228.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

Description

Low GERP score may suggest that this variant may belong in a lower pathogenicity class

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000549149.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 8 of the KCNE1 protein (p.Ala8Val). This variant is present in population databases (rs199473348, gnomAD 0.06%). This missense change has been observed in individual(s) with long QT syndrome or clinical suspicion of long QT syndrome (PMID: 17341399, 19716085, 31521807, 31535183, 34403091). ClinVar contains an entry for this variant (Variation ID: 132670). 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) performed at Invitae indicates that this missense variant is not expected to disrupt KCNE1 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects KCNE1 function (PMID: 17341399, 18776039, 24400172). 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.

#	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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