NM_000335.5(SCN5A):c.611C>T (p.Ala204Val) AND Brugada syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Sep 22, 2019
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:: RCV000058828.5

Allele description [Variation Report for NM_000335.5(SCN5A):c.611C>T (p.Ala204Val)]

NM_000335.5(SCN5A):c.611C>T (p.Ala204Val)

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.611C>T (p.Ala204Val)

HGVS:

NC_000003.12:g.38620843G>A
NG_008934.1:g.33830C>T
NM_000335.5:c.611C>TMANE SELECT
NM_001099404.2:c.611C>T
NM_001099405.2:c.611C>T
NM_001160160.2:c.611C>T
NM_001160161.2:c.611C>T
NM_001354701.2:c.611C>T
NM_198056.3:c.611C>T
NP_000326.2:p.Ala204Val
NP_001092874.1:p.Ala204Val
NP_001092875.1:p.Ala204Val
NP_001153632.1:p.Ala204Val
NP_001153633.1:p.Ala204Val
NP_001341630.1:p.Ala204Val
NP_932173.1:p.Ala204Val
NP_932173.1:p.Ala204Val
LRG_289t1:c.611C>T
LRG_289:g.33830C>T
LRG_289p1:p.Ala204Val
NC_000003.11:g.38662334G>A
NM_198056.2:c.611C>T
NM_198056.3:c.611C>T
Q14524:p.Ala204Val

Protein change:

A204V

Links:

UniProtKB: Q14524#VAR_074330; dbSNP: rs199473559

NCBI 1000 Genomes Browser:

rs199473559

Molecular consequence:

NM_000335.5:c.611C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.611C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.611C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.611C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.611C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.611C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.611C>T - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

functionally_normal [Sequence Ontology: SO:0002219] - Comment(s)

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
SCV000090348	Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	no classification provided	not provided	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 20129283, 22581653
SCV001410436	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 22, 2019)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 20129283, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000090348

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

no classification provided

not provided

germline

literature only

PubMed (2)
[See all records that cite these PMIDs]

SCV001410436

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 22, 2019)

germline

clinical testing

PubMed (2)
[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, literature only

Citations

PubMed

Paralogous annotation of disease-causing variants in long QT syndrome genes.

Ware JS, Walsh R, Cunningham F, Birney E, Cook SA.

Hum Mutat. 2012 Aug;33(8):1188-1191. doi: 10.1002/humu.22114. Epub 2012 Jun 7.

PubMed [citation]

PMID:: 22581653
PMCID:: PMC4640174

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

See all PubMed Citations (3)

Details of each submission

From Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust, SCV000090348.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

This variant has been reported as associated with Brugada syndrome in the following publications (PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001410436.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces alanine with valine at codon 204 of the SCN5A protein (p.Ala204Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in an individual referred for diagnostic testing for Brugada syndrome (PMID: 20129283). ClinVar contains an entry for this variant (Variation ID: 68028). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been 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: Sep 29, 2024

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