NM_000219.6(KCNE1):c.142C>T (p.Leu48Phe) AND Long QT syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jul 16, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001369414.4

Allele description [Variation Report for NM_000219.6(KCNE1):c.142C>T (p.Leu48Phe)]

NM_000219.6(KCNE1):c.142C>T (p.Leu48Phe)

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.142C>T (p.Leu48Phe)

HGVS:

NC_000021.9:g.34449493G>A
NG_009091.1:g.66823C>T
NM_000219.6:c.142C>TMANE SELECT
NM_001127668.4:c.142C>T
NM_001127669.4:c.142C>T
NM_001127670.4:c.142C>T
NM_001270402.3:c.142C>T
NM_001270403.2:c.142C>T
NM_001270404.3:c.142C>T
NM_001270405.3:c.142C>T
NP_000210.2:p.Leu48Phe
NP_001121140.1:p.Leu48Phe
NP_001121141.1:p.Leu48Phe
NP_001121142.1:p.Leu48Phe
NP_001257331.1:p.Leu48Phe
NP_001257332.1:p.Leu48Phe
NP_001257333.1:p.Leu48Phe
NP_001257334.1:p.Leu48Phe
LRG_290t1:c.142C>T
LRG_290:g.66823C>T
NC_000021.8:g.35821791G>A
NM_000219.3:c.142C>T

Protein change:

L48F

Links:

dbSNP: rs75610894

NCBI 1000 Genomes Browser:

rs75610894

Molecular consequence:

NM_000219.6:c.142C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127668.4:c.142C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127669.4:c.142C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127670.4:c.142C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001270402.3:c.142C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001270403.2:c.142C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001270404.3:c.142C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001270405.3:c.142C>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV001565853	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 16, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31337358, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001565853

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 16, 2023)

germline

clinical testing

PubMed (2)
[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

Citations

PubMed

Next-generation sequencing using microfluidic PCR enrichment for molecular autopsy.

Raju H, Ware JS, Skinner JR, Hedley PL, Arno G, Love DR, van der Werf C, Tfelt-Hansen J, Winkel BG, Cohen MC, Li X, John S, Sharma S, Jeffery S, Wilde AAM, Christiansen M, Sheppard MN, Behr ER.

BMC Cardiovasc Disord. 2019 Jul 23;19(1):174. doi: 10.1186/s12872-019-1154-8.

PubMed [citation]

PMID:: 31337358
PMCID:: PMC6651896

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV001565853.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 48 of the KCNE1 protein (p.Leu48Phe). This variant is present in population databases (rs75610894, gnomAD 0.006%). This missense change has been observed in individual(s) with sudden unexplained death (PMID: 31337358). ClinVar contains an entry for this variant (Variation ID: 1060040). 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.

#	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: Feb 20, 2024

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