ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.5767G>A (p.Ala1923Thr)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Likely pathogenic(1); Uncertain significance(3); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000335.5(SCN5A):c.5767G>A (p.Ala1923Thr)
Variation ID: 9381 Accession: VCV000009381.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 38550602 (GRCh38) [ NCBI UCSC ] 3: 38592093 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jun 9, 2014 Feb 14, 2024 Dec 29, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000335.5:c.5767G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000326.2:p.Ala1923Thr missense NM_001099404.2:c.5770G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001092874.1:p.Ala1924Thr missense NM_001099405.2:c.5716G>A NP_001092875.1:p.Ala1906Thr missense NM_001160160.2:c.5671G>A NP_001153632.1:p.Ala1891Thr missense NM_001160161.2:c.5608G>A NP_001153633.1:p.Ala1870Thr missense NM_001354701.2:c.5713G>A NP_001341630.1:p.Ala1905Thr missense NM_198056.3:c.5770G>A NP_932173.1:p.Ala1924Thr missense NC_000003.12:g.38550602C>T NC_000003.11:g.38592093C>T NG_008934.1:g.104071G>A LRG_289:g.104071G>A LRG_289t1:c.5770G>A LRG_289p1:p.Ala1924Thr - Protein change
- A1924T, A1923T, A1870T, A1891T, A1905T, A1906T
- Other names
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- Canonical SPDI
- NC_000003.12:38550601:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00003
Exome Aggregation Consortium (ExAC) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00006
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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SCN5A | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3554 | 3958 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Likely pathogenic (2) |
criteria provided, single submitter
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Dec 10, 2018 | RCV000009978.16 | |
not provided (1) |
criteria provided, single submitter
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- | RCV000058806.16 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Dec 29, 2023 | RCV000420298.13 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 22, 2023 | RCV001841233.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 6, 2021 | RCV002251424.9 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Dec 10, 2018)
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criteria provided, single submitter
Method: clinical testing
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Brugada syndrome 1
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000916016.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
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)
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 Brugada syndrome and in a homozygous state in a pair of identical twins affected with sinus node dysfunction (Rook et al. 1999; Meregalli et al. 2009; Amin et al. 2011; Chiang et al. 2015). The p.Ala1924Thr variant was present in one of 1400 controls (Kapplinger et al. 2010) and is reported at a frequency of 0.001084 in the Ashkenazi Jewish population of the Genome Aggregation Database. Functional studies in Xenopus oocytes demonstrated that the variant significantly affected the inward sodium current causing an increase during the action potential upstroke (Rook et al. 1999). Tan et al. (200) demonstrated that the p.Ala1924Thr increased the rate of fast activation of the sodium channel whilst inhibiting the slow activation induced by the calcium-dependent binding of calmodulin. Based on the evidence, the p.Ala1924Thr variant is classified as likely pathogenic for Brugada syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Uncertain significance
(Jan 15, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000514559.3
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
Comment:
Observed in several individuals with Brugada syndrome in the published literature (Rook et al., 1999; Smits et al., 2002; Tan et al., 2002; Meregalli et … (more)
Observed in several individuals with Brugada syndrome in the published literature (Rook et al., 1999; Smits et al., 2002; Tan et al., 2002; Meregalli et al., 2009; Kapplinger et al., 2010; Amin et al., 2011; Nof et al., 2019); Reported in ClinVar (ClinVar Variant ID# 9381; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25758664, 15795161, 16472137, 11893549, 27262167, 19171938, 12106943, 25904541, 33306788, 23104914, 17993328, 11673053, 19251209, 20129283, 21273195, 11807557, 11420310, 11123251, 12393785, 19027780, 14753626, 21454796, 10690282, 26111534, 9950665, 14961552, 11410597, 10940383, 12639704, 23414114, 31231243, 30662450, 21167176, 16505387, 33131149) (less)
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Uncertain significance
(Aug 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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Brugada syndrome
Long QT syndrome
Affected status: no
Allele origin:
germline
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National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health
Accession: SCV002522176.1
First in ClinVar: Jun 05, 2022 Last updated: Jun 05, 2022 |
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Likely benign
(Dec 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000637191.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024 |
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Uncertain significance
(Feb 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiac arrhythmia
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV001347318.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces alanine with threonine at codon 1924 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces alanine with threonine at codon 1924 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant affects sodium channel activation and inactivation properties (PMID: 10690282, 11807557, 23104914) and reduces binding affinity for calmodulin (PMID: 16505387). This variant has been reported in an individual affected with Brugada syndrome (PMID: 10690282), in homozygous identical twins with sinus node dysfunction and atrial tachycardia (PMID: 26111534), as well as in a control individual (PMID: 25904541). This variant has been identified in 16/280642 chromosomes (12/10352 Ashkenazi Jewish chromosomes, 0.11%) in the general population by the Genome Aggregation Database (gnomAD). In summary, although this variant has been reported in multiple affected individuals, this variant also occurs at an appreciable frequency in the general population. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Pathogenic
(Dec 01, 1999)
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no assertion criteria provided
Method: literature only
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BRUGADA SYNDROME 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000030199.3
First in ClinVar: Apr 04, 2013 Last updated: Nov 18, 2016 |
Comment on evidence:
For discussion of the ala1924-to-thr (A1924T) substitution in the SCN5A gene that was found in compound heterozygous state in 2 patients with Brugada syndrome (BRGDA1; … (more)
For discussion of the ala1924-to-thr (A1924T) substitution in the SCN5A gene that was found in compound heterozygous state in 2 patients with Brugada syndrome (BRGDA1; 601144) by Rook et al. (1999), see 600163.0011. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Brugada syndrome
Affected status: unknown
Allele origin:
germline
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Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust
Accession: SCV000090326.3
First in ClinVar: Oct 22, 2013 Last updated: Jun 09, 2014 |
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)
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 the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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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 |
Enhanced Classification of Brugada Syndrome-Associated and Long-QT Syndrome-Associated Genetic Variants in the SCN5A-Encoded Na(v)1.5 Cardiac Sodium Channel. | Kapplinger JD | Circulation. Cardiovascular genetics | 2015 | PMID: 25904541 |
Genetic engineering of somatic cells to study and improve cardiac function. | Kirkton RD | 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 | 2012 | PMID: 23104914 |
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 |
Calcium-dependent regulation of the voltage-gated sodium channel hH1: intrinsic and extrinsic sensors use a common molecular switch. | Shah VN | Proceedings of the National Academy of Sciences of the United States of America | 2006 | PMID: 16505387 |
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 |
Text-mined citations for rs137854603 ...
HelpRecord last updated Mar 17, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.