NM_000335.5(SCN5A):c.5225G>A (p.Gly1742Glu) AND Brugada syndrome 1

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Feb 2, 2022
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:: RCV004786350.1

Allele description [Variation Report for NM_000335.5(SCN5A):c.5225G>A (p.Gly1742Glu)]

NM_000335.5(SCN5A):c.5225G>A (p.Gly1742Glu)

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.5225G>A (p.Gly1742Glu)

HGVS:

NC_000003.12:g.38551144C>T
NG_008934.1:g.103529G>A
NM_000335.5:c.5225G>AMANE SELECT
NM_001099404.2:c.5228G>A
NM_001099405.2:c.5174G>A
NM_001160160.2:c.5129G>A
NM_001160161.2:c.5066G>A
NM_001354701.2:c.5171G>A
NM_198056.3:c.5228G>A
NP_000326.2:p.Gly1742Glu
NP_001092874.1:p.Gly1743Glu
NP_001092875.1:p.Gly1725Glu
NP_001153632.1:p.Gly1710Glu
NP_001153633.1:p.Gly1689Glu
NP_001341630.1:p.Gly1724Glu
NP_932173.1:p.Gly1743Glu
NP_932173.1:p.Gly1743Glu
LRG_289t1:c.5228G>A
LRG_289:g.103529G>A
LRG_289p1:p.Gly1743Glu
NC_000003.11:g.38592635C>T
NM_198056.2:c.5228G>A

Protein change:

G1689E

Links:

dbSNP: rs199473629

NCBI 1000 Genomes Browser:

rs199473629

Molecular consequence:

NM_000335.5:c.5225G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.5228G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.5174G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.5129G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.5066G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.5171G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.5228G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Brugada syndrome 1 (BRGDA1)
Synonyms:: RIGHT BUNDLE BRANCH BLOCK, ST SEGMENT ELEVATION, AND SUDDEN DEATH SYNDROME
Identifiers:: MONDO: MONDO:0011001; MedGen: C4551804; Orphanet: 130; OMIM: 601144

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV005399441	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 2, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 20129283, 30847665, 29798782, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV005399441

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 2, 2022)

germline

clinical testing

PubMed (4)
[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

An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing.

Kapplinger JD, Tester DJ, Alders M, Benito B, Berthet M, Brugada J, Brugada P, Fressart V, Guerchicoff A, Harris-Kerr C, Kamakura S, Kyndt F, Koopmann TT, Miyamoto Y, Pfeiffer R, Pollevick GD, Probst V, Zumhagen S, Vatta M, Towbin JA, Shimizu W, Schulze-Bahr E, et al.

Heart Rhythm. 2010 Jan;7(1):33-46. doi: 10.1016/j.hrthm.2009.09.069. Epub 2009 Oct 8.

PubMed [citation]

PMID:: 20129283
PMCID:: PMC2822446

Large next-generation sequencing gene panels in genetic heart disease: challenges in clinical practice.

Christiaans I, Mook ORF, Alders M, Bikker H, Lekanne Dit Deprez RH.

Neth Heart J. 2019 Jun;27(6):299-303. doi: 10.1007/s12471-019-1251-4.

PubMed [citation]

PMID:: 30847665
PMCID:: PMC6533326

See all PubMed Citations (4)

Details of each submission

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005399441.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are both known mechanisms of disease in this gene. Loss of function is usually associated with Brugada syndrome 1 (MIM#601144) and sick sinus syndrome 1 (SSS) (MIM#608567), whereas gain of function is usually associated with long QT syndrome-3 (LQTS) (MIM#603830). Dilated cardiomyopathy 1E (DCM) (MIM#601154) can be caused by variants with either a loss or gain of function mechanism (PMID: 29798782). (I) 0108 - This gene is associated with both recessive and dominant disease. Most conditions associated with this gene are dominantly inherited; however SSS is caused by biallelic variants (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to glutamic acid. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated ion transport domain (NCBI, DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple individuals with Brugada syndrome (PMIDs: 20129283, LOVD) and it has also been reported in an individual with a combination of restrictive and dilated cardiomyopathy (PMID: 30847665). (SP) 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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Mar 5, 2025

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