NM_000335.5(SCN5A):c.1127G>A (p.Arg376His) AND Cardiac arrhythmia

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Aug 8, 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:: RCV001842271.11

Allele description [Variation Report for NM_000335.5(SCN5A):c.1127G>A (p.Arg376His)]

NM_000335.5(SCN5A):c.1127G>A (p.Arg376His)

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.1127G>A (p.Arg376His)

Other names:

p.R376H:CGC>CAC

HGVS:

NC_000003.12:g.38606682C>T
NG_008934.1:g.47991G>A
NM_000335.5:c.1127G>AMANE SELECT
NM_001099404.2:c.1127G>A
NM_001099405.2:c.1127G>A
NM_001160160.2:c.1127G>A
NM_001160161.2:c.1127G>A
NM_001354701.2:c.1127G>A
NM_198056.3:c.1127G>A
NP_000326.2:p.Arg376His
NP_001092874.1:p.Arg376His
NP_001092875.1:p.Arg376His
NP_001153632.1:p.Arg376His
NP_001153633.1:p.Arg376His
NP_001341630.1:p.Arg376His
NP_932173.1:p.Arg376His
NP_932173.1:p.Arg376His
LRG_289t1:c.1127G>A
LRG_289:g.47991G>A
LRG_289p1:p.Arg376His
NC_000003.11:g.38648173C>T
NM_198056.2:c.1127G>A
NM_198056.3:c.1127G>A
Q14524:p.Arg376His

Protein change:

R376H

Links:

UniProtKB: Q14524#VAR_055169; dbSNP: rs199473101

NCBI 1000 Genomes Browser:

rs199473101

Molecular consequence:

NM_000335.5:c.1127G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.1127G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.1127G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.1127G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.1127G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.1127G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.1127G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cardiac arrhythmia
Synonyms:: Cardiac rhythm disease
Identifiers:: EFO: EFO_0004269; MONDO: MONDO:0007263; MedGen: C0003811; Human Phenotype Ontology: HP:0011675

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001359848	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 8, 2023)	germline	clinical testing	PubMed (14) [See all records that cite these PMIDs] 15851228, 16344400, 18378609, 20129283, 21840964, 23671135, 24295898, 25194972, 26713557, 27930701, 28341781, 29709101, 32893267, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001359848

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Aug 8, 2023)

germline

clinical testing

PubMed (14)
[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

Novel pore mutation in SCN5A manifests as a spectrum of phenotypes ranging from atrial flutter, conduction disease, and Brugada syndrome to sudden cardiac death.

Rossenbacker T, Carroll SJ, Liu H, Kuipéri C, de Ravel TJ, Devriendt K, Carmeliet P, Kass RS, Heidbüchel H.

Heart Rhythm. 2004 Nov;1(5):610-5.

PubMed [citation]

PMID:: 15851228

Cardiac histological substrate in patients with clinical phenotype of Brugada syndrome.

Frustaci A, Priori SG, Pieroni M, Chimenti C, Napolitano C, Rivolta I, Sanna T, Bellocci F, Russo MA.

Circulation. 2005 Dec 13;112(24):3680-7.

PubMed [citation]

PMID:: 16344400

See all PubMed Citations (14)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001359848.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (14)

Description

This missense variant replaces arginine with histidine at codon 376 of the SCN5A protein. This variant is found within the highly conserved pore-forming region of transmembrane domain DI (a.a. 277-389). Rare nontruncating variants in this region have been shown to be significantly overrepresented in individuals with Brugada syndrome (PMID: 32893267). Functional studies have shown that this variant significantly reduces sodium channel currents (PMID: 15851228, 21840964, 24295898, 26713557). This variant has shown a highly variable phenotypic presentation ranging from Brugada syndrome to conduction disease in 9 members from a single family (PMID: 15851228). This variant has been reported in multiple other individuals affected with Brugada syndrome or referred for Brugada syndrome genetic testing (PMID: 16344400, 20129283, 28341781, 29709101) in an individual affected with atrial fibrillation (PMID: 18378609) and in individuals affected with sudden death (PMID: 23671135, 25194972, 27930701). This variant has been identified in 2/247596 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

#	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: Oct 8, 2024

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