NM_172201.2(KCNE2):c.79C>T (p.Arg27Cys) AND Atrial fibrillation, familial, 4

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Nov 26, 2018
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:: RCV000006427.9

Allele description [Variation Report for NM_172201.2(KCNE2):c.79C>T (p.Arg27Cys)]

NM_172201.2(KCNE2):c.79C>T (p.Arg27Cys)

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.79C>T (p.Arg27Cys)

HGVS:

NC_000021.9:g.34370557C>T
NG_008804.1:g.11534C>T
NM_172201.2:c.79C>TMANE SELECT
NP_751951.1:p.Arg27Cys
NP_751951.1:p.Arg27Cys
LRG_291t1:c.79C>T
LRG_291:g.11534C>T
LRG_291p1:p.Arg27Cys
NC_000021.8:g.35742856C>T
NM_172201.1:c.79C>T
Q9Y6J6:p.Arg27Cys

Protein change:

R27C; ARG27CYS

Links:

UniProtKB: Q9Y6J6#VAR_037795; OMIM: 603796.0004; dbSNP: rs74315449

NCBI 1000 Genomes Browser:

rs74315449

Molecular consequence:

NM_172201.2:c.79C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Atrial fibrillation, familial, 4 (ATFB4)
Identifiers:: MONDO: MONDO:0012677; MedGen: C1862394; OMIM: 611493

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000026610	OMIM	no assertion criteria provided	Pathogenic (Nov 1, 2004)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 15368194, 24681347
SCV000914966	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Uncertain significance (Nov 26, 2018)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 24681347, 15368194, 16487223 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000026610

OMIM

no assertion criteria provided

Pathogenic
(Nov 1, 2004)

germline

literature only

PubMed (2)
[See all records that cite these PMIDs]

SCV000914966

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)

Uncertain significance
(Nov 26, 2018)

germline

clinical testing

PubMed (3)
[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	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

KCNE2 modulates cardiac L-type Ca(2+) channel.

Liu W, Deng J, Wang G, Zhang C, Luo X, Yan D, Su Q, Liu J.

J Mol Cell Cardiol. 2014 Jul;72:208-18. doi: 10.1016/j.yjmcc.2014.03.013. Epub 2014 Mar 26.

PubMed [citation]

PMID:: 24681347

Identification of a KCNE2 gain-of-function mutation in patients with familial atrial fibrillation.

Yang Y, Xia M, Jin Q, Bendahhou S, Shi J, Chen Y, Liang B, Lin J, Liu Y, Liu B, Zhou Q, Zhang D, Wang R, Ma N, Su X, Niu K, Pei Y, Xu W, Chen Z, Wan H, Cui J, Barhanin J, et al.

Am J Hum Genet. 2004 Nov;75(5):899-905. Epub 2004 Sep 13.

PubMed [citation]

PMID:: 15368194
PMCID:: PMC1182120

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000026610.2

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

Description

In a study of 28 unrelated Chinese kindreds with atrial fibrillation (611493), Yang et al. (2004) found that 2 of the probands had an arginine-to-cysteine change at codon 27 (R27C) of KCNE2, the beta-subunit of the KCNQ1-KCNE2 channel responsible for a background potassium current. The amino acid change resulted from a C-to-T transition at nucleotide position 79 from the translation initiation codon. The mutation was present in all affected members in the 2 kindreds and was absent in 462 healthy unrelated Chinese subjects. Similar to KCNQ1 S140G (607542.0032), the KCNE2 R27C mutation had a gain-of-function effect on the KCNQ1-KCNE2 channel.

By expression in rat ventricular myocytes, Liu et al. (2014) found that human KCNE2 with the R27C substitution was more effective than wildtype in suppressing Cav1.2 (CACNA1C; 114205)-dependent calcium currents. The mutation did not significantly change KCNE2 regulation of voltage-dependent activation and steady-stage voltage-dependent channel inactivation, nor did it alter expression of other calcium channel subunits.

#	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		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV000914966.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The KCNE2 c.79C>T (p.Arg27Cys) variant is a missense variant that has been reported in a heterozygous state in two unrelated Chinese individuals with atrial fibrillation (AF) (Yang et al. 2004). The affected mother of one of the patients also carried the variant. The deceased mother of the other patient was not tested but had a history of paroxysmal AF. Carrier siblings of the probands did not have AF at the time of testing but did have a history of apparent recurrent palpitations. The variant was identified in one out of a total of 727 Chinese control individuals (Yang et al. 2014; Koo et al. 2006) and is reported at a frequency of 0.000954 in the East Asian population of the Genome Aggregation Database. When expressed in HEK293 cells, Arg27Cys KCNE2 showed a gain of function effect, showing a greater suppressive effect on the L-type calcium channel current than wildtype KCNE2 (Liu et al. 2014). A gain of function effect on KCNQ1-KCNE2 channel function was also observed in COS-7 cells (Yang et al. 2004). The evidence for this variant is limited. The c.79C>T (p.Arg27Cys) variant is thus classified as of uncertain significance but suspicious for pathogenicity for familial atrial fibrillation. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	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: Sep 29, 2024

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