NM_172201.2(KCNE2):c.160A>G (p.Met54Val) AND Long QT syndrome 6

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jun 10, 2022
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:: RCV001208257.11

Allele description [Variation Report for NM_172201.2(KCNE2):c.160A>G (p.Met54Val)]

NM_172201.2(KCNE2):c.160A>G (p.Met54Val)

Genes:

KCNE2:potassium voltage-gated channel subfamily E regulatory subunit 2 [Gene - OMIM - HGNC]
LOC105372791:uncharacterized LOC105372791 [Gene]

Variant type:

single nucleotide variant

Cytogenetic location:

21q22.11

Genomic location:

Preferred name:

NM_172201.2(KCNE2):c.160A>G (p.Met54Val)

HGVS:

NC_000021.9:g.34370638A>G
NG_008804.1:g.11615A>G
NM_172201.2:c.160A>GMANE SELECT
NP_751951.1:p.Met54Val
LRG_291t1:c.160A>G
LRG_291:g.11615A>G
NC_000021.8:g.35742937A>G
NM_172201.1:c.160A>G

Protein change:

M54V

Links:

dbSNP: rs371724328

NCBI 1000 Genomes Browser:

rs371724328

Molecular consequence:

NM_172201.2:c.160A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Long QT syndrome 6 (LQT6)
Identifiers:: MONDO: MONDO:0013370; MedGen: C3150953; Orphanet: 101016; Orphanet: 768; OMIM: 613693

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001379635	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jun 10, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002766879	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 31, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 24796621, 26123744, 32078429, 33626434, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001379635

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jun 10, 2022)

germline

clinical testing

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

SCV002766879

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 31, 2022)

germline

clinical testing

PubMed (5)
[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	yes	not provided	not provided	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

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Gain-of-function mutations in potassium channel subunit KCNE2 associated with early-onset lone atrial fibrillation.

Nielsen JB, Bentzen BH, Olesen MS, David JP, Olesen SP, Haunsø S, Svendsen JH, Schmitt N.

Biomark Med. 2014;8(4):557-70. doi: 10.2217/bmm.13.137.

PubMed [citation]

PMID:: 24796621

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001379635.5

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

Description

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 54 of the KCNE2 protein (p.Met54Val). This variant is present in population databases (rs371724328, gnomAD 0.003%). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 938947). This variant has not been reported in the literature in individuals affected with KCNE2-related conditions.

#	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 Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002766879.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established, however loss- and gain of function are suggested mechanisms (PMID: 26123744, PMID: 24796621). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from methionine to valine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (3 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (69 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated ISK channel domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. However, an alternative change with a higher Grantham score, p.(Met54Thr), has been reported. This variant has been classified as a VUS, likely pathogenic and as a risk factor, and has been observed in several individuals with arrhythmia, sudden death, Brugada syndrome and long QT syndrome (ClinVar, PMID: 32078429, PMID: 33626434). (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported as a VUS (ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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

Last Updated: Sep 29, 2024

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