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NM_198056.2(SCN5A):c.5770G>A (p.Ala1924Thr)

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely pathogenic(2);Uncertain significance(1)

Review status:
criteria provided, conflicting interpretations
Submissions:
5 (Most recent: Feb 1, 2019)
Last evaluated:
Dec 10, 2018
Accession:
VCV000009381.3
Variation ID:
9381
Description:
single nucleotide variant
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NM_198056.2(SCN5A):c.5770G>A (p.Ala1924Thr)

Allele ID
24420
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
3p22.2
Genomic location
3: 38550602 (GRCh38) GRCh38 UCSC
3: 38592093 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
LRG_289:g.104071G>A
NC_000003.11:g.38592093C>T
NC_000003.12:g.38550602C>T
... more HGVS
Protein change
A1924T
Other names
-
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
The Genome Aggregation Database (gnomAD), exomes 0.00006
Exome Aggregation Consortium (ExAC) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00004
The Genome Aggregation Database (gnomAD) 0.00003
Links
ClinGen: CA019460
OMIM: 600163.0012
dbSNP: rs137854603
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Likely pathogenic 2 criteria provided, single submitter Dec 10, 2018 RCV000009978.5
Uncertain significance 2 criteria provided, single submitter Jun 14, 2017 RCV000058806.3
Likely pathogenic 1 criteria provided, single submitter Jul 7, 2016 RCV000420298.1
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
SCN5A Some evidence for dosage pathogenicity No evidence available GRCh38
GRCh37
1475 1633

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Uncertain significance
(Jun 14, 2017)
criteria provided, single submitter
Method: clinical testing
Brugada syndrome
Allele origin: germline
Invitae
Accession: SCV000637191.1
Submitted: (Oct 05, 2017)
Evidence details
Comment:
This sequence change replaces alanine with threonine at codon 1924 of the SCN5A protein (p.Ala1924Thr). The alanine residue is highly conserved and there is a ... (more)
Likely pathogenic
(Jul 07, 2016)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000514559.3
Submitted: (Jan 29, 2019)
Evidence details
Comment:
The likely pathogenic A1924T variant in the SCN5A gene has been reported in at least one heterozygous individual in association with Brugada syndrome and was ... (more)
Likely pathogenic
(Dec 10, 2018)
criteria provided, single submitter
Method: clinical testing
Brugada syndrome 1
Allele origin: germline
Illumina Clinical Services Laboratory,Illumina
Accession: SCV000916016.1
Submitted: (Feb 01, 2019)
Evidence details
Publications
PubMed (6)
Comment:
The SCN5A c.5770G>A (p.Ala1924Thr) missense variant has described in four studies and found in a heterozygous state in a total of three individuals affected with ... (more)
Pathogenic
(Dec 01, 1999)
no assertion criteria provided
Method: literature only
BRUGADA SYNDROME 1
Allele origin: germline
OMIM
Accession: SCV000030199.3
Submitted: (Dec 30, 2010)
Evidence details
Publications
PubMed (1)
not provided
(-)
no assertion provided
Method: literature only
Brugada syndrome
Allele origin: germline
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust
Accession: SCV000090326.3
Submitted: (Sep 22, 2016)
Evidence details
Publications
PubMed (5)
Comment:
This variant has been reported as associated with Brugada syndrome in the following publications (PMID:10690282;PMID:12106943;PMID:19251209;PMID:20129283). This is a literature report, and does not necessarily reflect ... (more)

Citations for this variant

Title Author Journal Year Link
Loss-of-Function SCN5A Mutations Associated With Sinus Node Dysfunction, Atrial Arrhythmias, and Poor Pacemaker Capture. Chiang DY Circulation. Arrhythmia and electrophysiology 2015 PMID: 26111534
Paralogous annotation of disease-causing variants in long QT syndrome genes. Ware JS Human mutation 2012 PMID: 22581653
Facilitatory and inhibitory effects of SCN5A mutations on atrial fibrillation in Brugada syndrome. Amin AS Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology 2011 PMID: 21273195
An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing. Kapplinger JD Heart rhythm 2010 PMID: 20129283
Type of SCN5A mutation determines clinical severity and degree of conduction slowing in loss-of-function sodium channelopathies. Meregalli PG Heart rhythm 2009 PMID: 19251209
Genotype-phenotype relationship in Brugada syndrome: electrocardiographic features differentiate SCN5A-related patients from non-SCN5A-related patients. Smits JP Journal of the American College of Cardiology 2002 PMID: 12106943
A calcium sensor in the sodium channel modulates cardiac excitability. Tan HL Nature 2002 PMID: 11807557
Human SCN5A gene mutations alter cardiac sodium channel kinetics and are associated with the Brugada syndrome. Rook MB Cardiovascular research 1999 PMID: 10690282

Record last updated Oct 27, 2019