NM_000335.5(SCN5A):c.664C>T (p.Arg222Ter) AND Brugada syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Sep 18, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV003996808.3

Allele description [Variation Report for NM_000335.5(SCN5A):c.664C>T (p.Arg222Ter)]

NM_000335.5(SCN5A):c.664C>T (p.Arg222Ter)

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.664C>T (p.Arg222Ter)

Other names:

p.R222X:CGA>TGA

HGVS:

NC_000003.12:g.38613782G>A
NG_008934.1:g.40891C>T
NM_000335.5:c.664C>TMANE SELECT
NM_001099404.2:c.703+193C>T
NM_001099405.2:c.703+193C>T
NM_001160160.2:c.703+193C>T
NM_001160161.2:c.703+193C>T
NM_001354701.2:c.703+193C>T
NM_198056.3:c.664C>T
NP_000326.2:p.Arg222Ter
NP_932173.1:p.Arg222Ter
NP_932173.1:p.Arg222Ter
LRG_289t1:c.664C>T
LRG_289:g.40891C>T
LRG_289p1:p.Arg222Ter
NC_000003.11:g.38655273G>A
NM_198056.2:c.664C>T

Protein change:

R222*

Links:

dbSNP: rs794728849

NCBI 1000 Genomes Browser:

rs794728849

Molecular consequence:

NM_001099404.2:c.703+193C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001099405.2:c.703+193C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001160160.2:c.703+193C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001160161.2:c.703+193C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001354701.2:c.703+193C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000335.5:c.664C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_198056.3:c.664C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Brugada syndrome
Synonyms:: Sudden unexpected nocturnal death syndrome; Sudden unexplained nocturnal death syndrome; Sudden Unexplained Death Syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015263; MedGen: C1142166; OMIM: PS601144

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004843403	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 18, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 22277643, 26173111, 26467377, 27232914, 27287068, 32893267, 34546463, 25741868
SCV005045706	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 17, 2019)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004843403

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Sep 18, 2023)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV005045706

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Dec 17, 2019)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	108544	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Criteria to predict carriers of a novel SCN5A mutation in a large Portuguese family affected by the Brugada syndrome.

Santos LF, Rodrigues B, Moreira D, Correia E, Nunes L, Costa A, Elvas L, Pereira T, Machado JC, Castedo S, Henriques C, Matos A, Santos JO.

Europace. 2012 Jun;14(6):882-8. doi: 10.1093/europace/eur421. Epub 2012 Jan 25.

PubMed [citation]

PMID:: 22277643

Comprehensive Genetic Characterization of a Spanish Brugada Syndrome Cohort.

Selga E, Campuzano O, Pinsach-Abuin ML, Pérez-Serra A, Mademont-Soler I, Riuró H, Picó F, Coll M, Iglesias A, Pagans S, Sarquella-Brugada G, Berne P, Benito B, Brugada J, Porres JM, López Zea M, Castro-Urda V, Fernández-Lozano I, Brugada R.

PLoS One. 2015;10(7):e0132888. doi: 10.1371/journal.pone.0132888.

PubMed [citation]

PMID:: 26173111
PMCID:: PMC4501715

See all PubMed Citations (8)

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004843403.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (8)

Description

This variant changes 1 nucleotide in exon 6 of the SCN5A gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A functional study has shown that this variant causes a large reduction of sodium current amplitudes when expressed in Xenopus oocytes (PMID 27287068). This variant has been reported in at least five families affected with Brugada syndrome (PMID: 22277643, 26173111, 26467377, 27232914, 27287068, 32893267, 34546463). Asymptomatic carriers were also reported in a few families (PMID: 22277643, 26467377). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of SCN5A function is a known mechanism of disease (clinicalgenome.org). 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	108544	not provided	not provided		1	not provided	not provided	not provided

From Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine, SCV005045706.1

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

Description

This c.664C>T (p.Arg222*) variant in the SCN5A gene introduces a premature translation termination codon. This variant has been observed in multiple individuals with Brugada syndrome as well as one individual tested for Long QT syndrome (PMID 26173111, 20129283, 27287068, 27232914, and 26467377). Based on the current evidence, this variant in the SCN5A gene is classified as pathogenic.

#	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

Last Updated: Oct 13, 2024

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