ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.1100G>A (p.Arg367His)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000335.5(SCN5A):c.1100G>A (p.Arg367His)
Variation ID: 9390 Accession: VCV000009390.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 38606709 (GRCh38) [ NCBI UCSC ] 3: 38648200 (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 Oct 8, 2024 Dec 16, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000335.5:c.1100G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000326.2:p.Arg367His missense NM_001099404.2:c.1100G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001092874.1:p.Arg367His missense NM_001099404.1:c.1100G>A NM_001099405.2:c.1100G>A NP_001092875.1:p.Arg367His missense NM_001160160.2:c.1100G>A NP_001153632.1:p.Arg367His missense NM_001160161.2:c.1100G>A NP_001153633.1:p.Arg367His missense NM_001354701.2:c.1100G>A NP_001341630.1:p.Arg367His missense NM_198056.3:c.1100G>A NP_932173.1:p.Arg367His missense NC_000003.12:g.38606709C>T NC_000003.11:g.38648200C>T NG_008934.1:g.47964G>A LRG_289:g.47964G>A LRG_289t1:c.1100G>A LRG_289p1:p.Arg367His LRG_289t3:c.1100G>A Q14524:p.Arg367His - Protein change
- R367H
- Other names
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- Canonical SPDI
- NC_000003.12:38606708: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
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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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 |
3779 | 4219 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Pathogenic (2) |
criteria provided, single submitter
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Jun 28, 2017 | RCV000009988.14 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 18, 2016 | RCV000058390.20 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 21, 2019 | RCV001841237.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 1, 2023 | RCV002426498.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 16, 2023 | RCV003654174.2 | |
SCN5A-related disorder
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Pathogenic (1) |
no assertion criteria provided
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Sep 10, 2024 | RCV004734509.1 |
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
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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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Pathogenic
(Jun 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Brugada syndrome 1
Affected status: yes
Allele origin:
unknown
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Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues
Accession: SCV000611768.1
First in ClinVar: Nov 18, 2016 Last updated: Nov 18, 2016 |
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Pathogenic
(Nov 18, 2016)
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criteria provided, single submitter
Method: clinical testing
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Brugada syndrome
Affected status: yes
Allele origin:
germline
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Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000740419.1
First in ClinVar: Apr 14, 2018 Last updated: Apr 14, 2018 |
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Pathogenic
(Mar 21, 2019)
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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: SCV001339601.2
First in ClinVar: Jun 22, 2020 Last updated: Jan 12, 2022 |
Comment:
This missense variant replaces arginine with histidine at codon 367 in the pore-forming region of transmembrane domain DI of the SCN5A protein. Computational prediction tools … (more)
This missense variant replaces arginine with histidine at codon 367 in the pore-forming region of transmembrane domain DI of the SCN5A protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. Experimental studies have shown that the mutant protein failed to generate sodium current in heterologous expression studies, despite normal channel protein trafficking to the cell membrane (PMID: 11823453, 14687250, 15028074, 22028457, 29024690). This variant has been shown to segregate with disease in a large Spanish family affected with familial Brugada syndrome (PMID: 15028074). This variant has been reported in over ten unrelated individuals affected with or suspected of having Brugada syndrome (PMID: 14753626, 17697823, 20129283, 26173111, 28341781), five individuals affected with sudden death (PMID: 11823453, 15028074, 24529773), two individuals affected with ventricular fibrillation (PMID: 22028457, 28912206), and in an individual affected with isolated atrioventricular block (PMID: 22899775). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at this codon (p.Arg367Cys) is associated with disease, suggesting the importance of this position in the sodium channel function (Clinvar variation ID: 67633). Based on available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Dec 16, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000545084.8
First in ClinVar: Jun 09, 2014 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 367 of the SCN5A protein (p.Arg367His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 367 of the SCN5A protein (p.Arg367His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Brugada syndrome (PMID: 11823453, 14753626, 17697823, 20129283, 22028457, 22899775, 24529773, 26173111). ClinVar contains an entry for this variant (Variation ID: 9390). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SCN5A function (PMID: 11823453, 21840964, 25348405). This variant disrupts the p.Arg367 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20129283, 21273195). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002740855.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.R367H pathogenic mutation (also known as c.1100G>A), located in coding exon 8 of the SCN5A gene, results from a G to A substitution at … (more)
The p.R367H pathogenic mutation (also known as c.1100G>A), located in coding exon 8 of the SCN5A gene, results from a G to A substitution at nucleotide position 1100. The arginine at codon 367 is replaced by histidine, an amino acid with highly similar properties. This alteration has been described in association with Brugada syndrome, cardiac conduction defects, and sudden death (Vatta M et al. Hum Mol Genet. 2002;11:337-45; Takehara N et al. J Intern Med. 2004;255:137-42). In one study, this alteration was detected in multiple relatives in a family with Brugada syndrome (Hong K et al. J Cardiovasc Electrophysiol. 2004;15:64-9). In several functional in vitro analyses, this alteration has demonstrated adverse effects resulting in absent sodium channel current (Vatta et al, 2002). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Feb 01, 2002)
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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: SCV000030209.4
First in ClinVar: Apr 04, 2013 Last updated: Nov 18, 2016 |
Comment on evidence:
Sudden unexplained nocturnal death syndrome (SUNDS), a disorder found in southeast Asia, is characterized by an abnormal electrocardiogram with ST segment elevation in leads V1 … (more)
Sudden unexplained nocturnal death syndrome (SUNDS), a disorder found in southeast Asia, is characterized by an abnormal electrocardiogram with ST segment elevation in leads V1 to V3 and sudden death due to ventricular fibrillation, identical to that seen in Brugada syndrome (BRGDA1; 601144). Vatta et al. (2002) found mutations in the SCN5A gene in 3 of 10 Asian SUNDS patients. In a sporadic Asian SUNDS patient, the authors identified a 1100G-A transition in SCN5A. The mutation is predicted to result in an arg367-to-his (R367H) substitution, which lies in the first P segment of the pore-lining region between the DIS5 and DIS6 transmembrane segments. In transfected Xenopus oocytes, the R367H mutant channel did not express any current. The authors hypothesized that the likely effect of this mutation is to depress peak current due to the loss of one functional allele. (less)
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Pathogenic
(Sep 10, 2024)
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no assertion criteria provided
Method: clinical testing
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SCN5A-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV005360762.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The SCN5A c.1100G>A variant is predicted to result in the amino acid substitution p.Arg367His. This variant has been reported in at least 8 unrelated individuals … (more)
The SCN5A c.1100G>A variant is predicted to result in the amino acid substitution p.Arg367His. This variant has been reported in at least 8 unrelated individuals with Brugada syndrome (Hong et al. 2004. PubMed ID: 15520322; Takehara et al. 2004. PubMed ID: 14687250; Kapplinger et al. 2010. PubMed ID: 20129283), in an individual with sudden unexplained death in which the variant was apparently de novo (Vatta et al. 2002. PubMed ID: 11823453), and in an individual with an AV block (Baruteau et al. 2012. PubMed ID: 22899775). The variant was found in 18 individuals in one family, of which 15 had ECGs consistent with Brugada syndrome either at baseline or when treated with a sodium channel blocker (Hong et al. 2004. PubMed ID: 15520322). Functional studies in Xenopus oocytes and in induced pluripotent stem cells indicate this variant results in a loss of channel current (Vatta et al. 2002. PubMed ID: 11823453; Takehara et al. 2004. PubMed ID: 14687250; Selga et al. 2018. PubMed ID: 29024690). Alternate nucleotide changes affecting the same amino acid have been reported in individuals with Brugada syndrome (p.Arg367Leu) and in both Brugada syndrome and Long QT syndrome (p.Arg367Cys) (Kapplinger et al. 2015. PubMed ID: 25904541). This variant has not been reported in a large population database, indicating it is rare. This variant is interpreted as pathogenic. (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: SCV000089910.3
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:11823453;PMID:14687250;PMID:15028074;PMID:19251209;PMID:22028457;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:11823453;PMID:14687250;PMID:15028074;PMID:19251209;PMID:22028457;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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Comprehensive Genetic Characterization of a Spanish Brugada Syndrome Cohort. | Selga E | PloS one | 2015 | PMID: 26173111 |
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 |
UniProt: a hub for protein information. | UniProt Consortium | Nucleic acids research | 2015 | PMID: 25348405 |
Is sudden unexplained nocturnal death syndrome in Southern China a cardiac sodium channel dysfunction disorder? | Liu C | Forensic science international | 2014 | PMID: 24529773 |
Parental electrocardiographic screening identifies a high degree of inheritance for congenital and childhood nonimmune isolated atrioventricular block. | Baruteau AE | Circulation | 2012 | PMID: 22899775 |
Electrocardiographic characteristics and SCN5A mutations in idiopathic ventricular fibrillation associated with early repolarization. | Watanabe H | Circulation. Arrhythmia and electrophysiology | 2011 | PMID: 22028457 |
A novel strategy using cardiac sodium channel polymorphic fragments to rescue trafficking-deficient SCN5A mutations. | Shinlapawittayatorn K | Circulation. Cardiovascular genetics | 2011 | PMID: 21840964 |
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 |
Comparison of long-term follow-up of electrocardiographic features in Brugada syndrome between the SCN5A-positive probands and the SCN5A-negative probands. | Yokokawa M | The American journal of cardiology | 2007 | PMID: 17697823 |
Phenotypic characterization of a large European family with Brugada syndrome displaying a sudden unexpected death syndrome mutation in SCN5A: | Hong K | Journal of cardiovascular electrophysiology | 2004 | PMID: 15028074 |
A cardiac sodium channel mutation identified in Brugada syndrome associated with atrial standstill. | Takehara N | Journal of internal medicine | 2004 | PMID: 14687250 |
The implications of genetic mutations in the sodium channel gene (SCN5A). | Moric E | 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 | 2003 | PMID: 14753626 |
Genetic and biophysical basis of sudden unexplained nocturnal death syndrome (SUNDS), a disease allelic to Brugada syndrome. | Vatta M | Human molecular genetics | 2002 | PMID: 11823453 |
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Text-mined citations for rs28937318 ...
HelpRecord last updated Oct 13, 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.