NM_000335.5(SCN5A):c.481G>A (p.Glu161Lys) AND Cardiovascular phenotype

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Aug 10, 2019
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:: RCV002336213.2

Allele description [Variation Report for NM_000335.5(SCN5A):c.481G>A (p.Glu161Lys)]

NM_000335.5(SCN5A):c.481G>A (p.Glu161Lys)

Gene:

SCN5A:sodium voltage-gated channel alpha subunit 5 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000335.5(SCN5A):c.481G>A (p.Glu161Lys)

HGVS:

NC_000003.12:g.38622401C>T
NG_008934.1:g.32272G>A
NM_000335.5:c.481G>AMANE SELECT
NM_001099404.2:c.481G>A
NM_001099405.2:c.481G>A
NM_001160160.2:c.481G>A
NM_001160161.2:c.481G>A
NM_001354701.2:c.481G>A
NM_198056.3:c.481G>A
NP_000326.2:p.Glu161Lys
NP_001092874.1:p.Glu161Lys
NP_001092875.1:p.Glu161Lys
NP_001153632.1:p.Glu161Lys
NP_001153633.1:p.Glu161Lys
NP_001341630.1:p.Glu161Lys
NP_932173.1:p.Glu161Lys
NP_932173.1:p.Glu161Lys
LRG_289t1:c.481G>A
LRG_289:g.32272G>A
LRG_289p1:p.Glu161Lys
NC_000003.11:g.38663892C>T
NM_198056.2:c.481G>A
Q14524:p.Glu161Lys

Protein change:

E161K

Links:

UniProtKB: Q14524#VAR_026344; dbSNP: rs199473062

NCBI 1000 Genomes Browser:

rs199473062

Molecular consequence:

NM_000335.5:c.481G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.481G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.481G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.481G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.481G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.481G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.481G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002635045	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Aug 10, 2019)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 12106943, 15910881, 19251209, 20031634, 20129283, 20384651, 20448214, 20539757, 21273195, 23414114, 29574140 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002635045

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Aug 10, 2019)

germline

clinical testing

PubMed (11)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Genotype-phenotype relationship in Brugada syndrome: electrocardiographic features differentiate SCN5A-related patients from non-SCN5A-related patients.

Smits JP, Eckardt L, Probst V, Bezzina CR, Schott JJ, Remme CA, Haverkamp W, Breithardt G, Escande D, Schulze-Bahr E, LeMarec H, Wilde AA.

J Am Coll Cardiol. 2002 Jul 17;40(2):350-6.

PubMed [citation]

PMID:: 12106943

A mutation in the human cardiac sodium channel (E161K) contributes to sick sinus syndrome, conduction disease and Brugada syndrome in two families.

Smits JP, Koopmann TT, Wilders R, Veldkamp MW, Opthof T, Bhuiyan ZA, Mannens MM, Balser JR, Tan HL, Bezzina CR, Wilde AA.

J Mol Cell Cardiol. 2005 Jun;38(6):969-81. Epub 2005 Apr 1.

PubMed [citation]

PMID:: 15910881

See all PubMed Citations (11)

Details of each submission

From Ambry Genetics, SCV002635045.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

The p.E161K pathogenic mutation (also known as c.481G>A), located in coding exon 3 of the SCN5A gene, results from a G to A substitution at nucleotide position 481. The glutamic acid at codon 161 is replaced by lysine, an amino acid with similar properties. This alteration has been identified in multiple unrelated individuals with arrythmogenic phenotypes, including Brugada syndrome, sick sinus syndrome, and conduction disease (Kapplinger JD et al. Heart Rhythm, 2010 Jan;7:33-46; Sonoda K et al. Heart Rhythm, 2018 08;15:1179-1188). It has been reported to segregate with disease in two families; however, one genotype-negative individual did exhibit a flecainide-induced Brugada pattern on ECG (Smits JP et al. J. Mol. Cell. Cardiol., 2005 Jun;38:969-81). Several functional studies indicate that E161K results in reduced sodium current in mammalian cells (Smits JP et al. J. Mol. Cell. Cardiol., 2005 Jun;38:969-81; Gui J et al. PLoS ONE, 2010 Jun;5:e10985). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#	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: May 1, 2024

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