NM_000335.5(SCN5A):c.4744C>T (p.Arg1582Cys) AND Cardiac arrhythmia

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Nov 27, 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:: RCV001842368.11

Allele description [Variation Report for NM_000335.5(SCN5A):c.4744C>T (p.Arg1582Cys)]

NM_000335.5(SCN5A):c.4744C>T (p.Arg1582Cys)

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.4744C>T (p.Arg1582Cys)

HGVS:

NC_000003.12:g.38554345G>A
NG_008934.1:g.100328C>T
NM_000335.5:c.4744C>TMANE SELECT
NM_001099404.2:c.4747C>T
NM_001099405.2:c.4693C>T
NM_001160160.2:c.4714+30C>T
NM_001160161.2:c.4585C>T
NM_001354701.2:c.4690C>T
NM_198056.3:c.4747C>T
NP_000326.2:p.Arg1582Cys
NP_001092874.1:p.Arg1583Cys
NP_001092875.1:p.Arg1565Cys
NP_001153633.1:p.Arg1529Cys
NP_001341630.1:p.Arg1564Cys
NP_932173.1:p.Arg1583Cys
NP_932173.1:p.Arg1583Cys
LRG_289t1:c.4747C>T
LRG_289:g.100328C>T
LRG_289p1:p.Arg1583Cys
NC_000003.11:g.38595836G>A
NM_198056.2:c.4747C>T
Q14524:p.Arg1583Cys

Protein change:

R1529C

Links:

UniProtKB: Q14524#VAR_074456; dbSNP: rs45514691

NCBI 1000 Genomes Browser:

rs45514691

Molecular consequence:

NM_001160160.2:c.4714+30C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000335.5:c.4744C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.4747C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.4693C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.4585C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.4690C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.4747C>T - 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
SCV000992458	Institute of Human Genetics, University of Wuerzburg	no assertion criteria provided	Likely pathogenic	unknown	clinical testing
SCV001350456	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 27, 2023)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 20129283, 24136861, 25650408, 25904541, 30193851, 31453232, 32533946, 32659924, 32893267, 34147702, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000992458

Institute of Human Genetics, University of Wuerzburg

no assertion criteria provided

Likely pathogenic

unknown

clinical testing

SCV001350456

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 27, 2023)

germline

clinical testing

PubMed (11)
[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
not provided	unknown	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

Paralogue annotation identifies novel pathogenic variants in patients with Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia.

Walsh R, Peters NS, Cook SA, Ware JS.

J Med Genet. 2014 Jan;51(1):35-44. doi: 10.1136/jmedgenet-2013-101917. Epub 2013 Oct 17.

PubMed [citation]

PMID:: 24136861
PMCID:: PMC3888601

See all PubMed Citations (11)

Details of each submission

From Institute of Human Genetics, University of Wuerzburg, SCV000992458.1

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

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

From Color Diagnostics, LLC DBA Color Health, SCV001350456.3

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

Description

This missense variant replaces arginine with cysteine at codon 1583 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant is found within a highly conserved region of the transmembrane domain DIV. Rare nontruncating variants in this region (a.a. 1530 -1771) have been shown to be significantly overrepresented in individuals with Brugada syndrome (PMID: 32893267). A functional study has shown that this variant causes a reduction in channel peak current density in transfected cells (PMID: 32533946). This variant has been reported in several individuals affected with Brugada syndrome or suspected of having Brugada syndrome (PMID: 20129283, 25650408, 30193851, 32659924, 32893267). This variant has also been reported in an individual affected with an inherited arrhythmia (Mizusawa 2016, thesis, University of Amsterdam), as well as in another individual affected with sudden cardiac death, who also carried a pathogenic splicing variant in the LMNA gene (PMID: 31453232). This variant has been identified in 2/249188 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, Arg1583His, has also been reported in a few individuals affected with Brugada syndrome (PMID: 24136861, 25904541, 32893267, 34147702), indicating that arginine at this position is important for SCN5A protein function. Although there is a suspicion for a pathogenic role, the available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	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 13, 2024

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