NM_000335.5(SCN5A):c.2204C>T (p.Ala735Val) AND Brugada syndrome 1

Germline classification:: Likely pathogenic (2 submissions)
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:: RCV000009989.5

Allele description [Variation Report for NM_000335.5(SCN5A):c.2204C>T (p.Ala735Val)]

NM_000335.5(SCN5A):c.2204C>T (p.Ala735Val)

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.2204C>T (p.Ala735Val)

HGVS:

NC_000003.12:g.38597787G>A
NG_008934.1:g.56886C>T
NM_000335.5:c.2204C>TMANE SELECT
NM_001099404.2:c.2204C>T
NM_001099405.2:c.2204C>T
NM_001160160.2:c.2204C>T
NM_001160161.2:c.2204C>T
NM_001354701.2:c.2204C>T
NM_198056.3:c.2204C>T
NP_000326.2:p.Ala735Val
NP_001092874.1:p.Ala735Val
NP_001092875.1:p.Ala735Val
NP_001153632.1:p.Ala735Val
NP_001153633.1:p.Ala735Val
NP_001341630.1:p.Ala735Val
NP_932173.1:p.Ala735Val
NP_932173.1:p.Ala735Val
LRG_289t1:c.2204C>T
LRG_289:g.56886C>T
LRG_289p1:p.Ala735Val
NC_000003.11:g.38639278G>A
NM_001099404.2:c.2204C>T
NM_198056.2:c.2204C>T
Q14524:p.Ala735Val

Protein change:

A735V; ALA735VAL

Links:

UniProtKB: Q14524#VAR_017674; OMIM: 600163.0022; dbSNP: rs137854611

NCBI 1000 Genomes Browser:

rs137854611

Molecular consequence:

NM_000335.5:c.2204C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.2204C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.2204C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.2204C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.2204C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.2204C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.2204C>T - 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
SCV000030210	OMIM	no assertion criteria provided	Pathogenic (Feb 1, 2002)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV005201047	Institute for Human Genetics and Genomic Medicine, Uniklinik RWTH Aachen	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	paternal	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

SCV000030210

OMIM

no assertion criteria provided

Pathogenic
(Feb 1, 2002)

germline

literature only

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

SCV005201047

Institute for Human Genetics and Genomic Medicine, Uniklinik RWTH Aachen

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic

paternal

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	paternal	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Genetic and biophysical basis of sudden unexplained nocturnal death syndrome (SUNDS), a disease allelic to Brugada syndrome.

Vatta M, Dumaine R, Varghese G, Richard TA, Shimizu W, Aihara N, Nademanee K, Brugada R, Brugada J, Veerakul G, Li H, Bowles NE, Brugada P, Antzelevitch C, Towbin JA.

Hum Mol Genet. 2002 Feb 1;11(3):337-45.

PubMed [citation]

PMID:: 11823453

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From OMIM, SCV000030210.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a family with SUNDS, a disorder identical to Brugada syndrome (BRGDA1; 601144), that exhibited autosomal dominant inheritance, Vatta et al. (2002) identified among affected members a 2204C-T transition, which is predicted to result in an ala735-to-val (A735V) substitution. The mutation lies in the first transmembrane segment of domain II, (DIIS1), close to the first extracellular loop between DIIS1 and DIIS2. In transfected Xenopus oocytes, the A735V mutant expressed currents with steady-state activation voltage shifted to more positive potentials and exhibited reduced sodium channel current at the end of phase I of the action potential.

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

From Institute for Human Genetics and Genomic Medicine, Uniklinik RWTH Aachen, SCV005201047.1

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

Description

The variant is present in the general population with a frequency of 0,000123%. Bioinformatic prediticon anticipate a deleterious effect, and it has been reported in patients with Brugada-syndrome before.

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

Last Updated: Sep 29, 2024

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