NM_000335.5(SCN5A):c.2204C>T (p.Ala735Val) AND Congenital long QT syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: May 31, 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:: RCV003996084.2

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]

Observations:

Condition(s)

Name:: Congenital long QT syndrome (RWS)
Synonyms:: Familial long QT syndrome; Romano-Ward syndrome; Ventricular fibrillation with prolonged QT interval
Identifiers:: MONDO: MONDO:0019171; MedGen: C1141890; Orphanet: 768; OMIM: PS192500

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004827566	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (May 31, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 11823453, 17697823, 20129283, 22795782, 26283144, 28491738, 36129056, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004827566

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(May 31, 2023)

germline

clinical testing

PubMed (8)
[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	1	not provided	not provided	108544	not provided	clinical testing

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

Comparison of long-term follow-up of electrocardiographic features in Brugada syndrome between the SCN5A-positive probands and the SCN5A-negative probands.

Yokokawa M, Noda T, Okamura H, Satomi K, Suyama K, Kurita T, Aihara N, Kamakura S, Shimizu W.

Am J Cardiol. 2007 Aug 15;100(4):649-55. Epub 2007 Jun 27.

PubMed [citation]

PMID:: 17697823

See all PubMed Citations (8)

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004827566.1

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

Description

The c.2204C>T (p.Ala735Val) variant in the SCN5A gene is located on the exon 14 and is predicted to replace alanine with valine at codon 735 (p.Ala735Val). The variant has been reported in multiple individuals with Brugada syndrome, in one individual with cardiac sinus node dysfunction and in one individual with dilated cardiomyopathy/other cardiac disease (PMID: 11823453, 17697823, 20129283, 22795782, 36129056, 28491738). The variant has been reported to segregate with Brugada syndrome in one family (PMID: 11823453). Electrophysiological experiments of this variant reported the negative functional impact (PMID: 11823453, 26283144). The variant is reported in ClinVar (ID: 9391). This variant is rare in the general population according to gnomAD (1/249112). Computational prediction algorithms suggest a deleterious impact for this variant (REVEL score 0.943). Therefore, the c.2204C>T (p.Ala735Val) variant of SCN5A has been classified as likely 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

Last Updated: Sep 29, 2024

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