ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.1099C>T (p.Arg367Cys)
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.1099C>T (p.Arg367Cys)
Variation ID: 67633 Accession: VCV000067633.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 38606710 (GRCh38) [ NCBI UCSC ] 3: 38648201 (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 Oct 9, 2016 May 1, 2024 Feb 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000335.5:c.1099C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000326.2:p.Arg367Cys missense NM_001099404.2:c.1099C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001092874.1:p.Arg367Cys missense NM_001099405.2:c.1099C>T NP_001092875.1:p.Arg367Cys missense NM_001160160.2:c.1099C>T NP_001153632.1:p.Arg367Cys missense NM_001160161.2:c.1099C>T NP_001153633.1:p.Arg367Cys missense NM_001354701.2:c.1099C>T NP_001341630.1:p.Arg367Cys missense NM_198056.3:c.1099C>T NP_932173.1:p.Arg367Cys missense NC_000003.12:g.38606710G>A NC_000003.11:g.38648201G>A NG_008934.1:g.47963C>T LRG_289:g.47963C>T LRG_289t1:c.1099C>T LRG_289p1:p.Arg367Cys LRG_289t3:c.1099C>T Q14524:p.Arg367Cys - Protein change
- R367C
- Other names
- p.R367C:CGC>TGC
- Canonical SPDI
- NC_000003.12:38606709:G:A
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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.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
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
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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 |
3739 | 4175 |
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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Apr 27, 2023 | RCV000058389.6 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 28, 2023 | RCV000182957.6 | |
Likely pathogenic (1) |
criteria provided, multiple submitters, no conflicts
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Feb 22, 2021 | RCV000466350.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000763108.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 1, 2024 | RCV002444519.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 5, 2022 | RCV001824120.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 23, 2024 | RCV003987345.1 |
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
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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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Progressive familial heart block, type 1A
SUDDEN INFANT DEATH SYNDROME Brugada syndrome 1 Dilated cardiomyopathy 1E Ventricular fibrillation, paroxysmal familial, type 1 Long QT syndrome 3 Sick sinus syndrome 1 Atrial fibrillation, familial, 10
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893650.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(Aug 28, 2023)
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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: SCV000235354.8
First in ClinVar: Jul 05, 2015 Last updated: Sep 07, 2023 |
Comment:
Reported in several unrelated individuals with definitive or suspected Brugada syndrome, LQTS, primary electrical disease, or unexplained cardiac arrest (Smits et al., 2002; Meregalli et … (more)
Reported in several unrelated individuals with definitive or suspected Brugada syndrome, LQTS, primary electrical disease, or unexplained cardiac arrest (Smits et al., 2002; Meregalli et al., 2009; Kapplinger et al., 2009; Kapplinger et al., 2010; Amin et al., 2011; Mellor et al., 2017); Published functional studies demonstrate a damaging effect as this variant results in reduction of the sodium current (Meregalli et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19716085, 19251209, 21273195, 24136861, 12106943, 20129283, 28341588, 28600387, 30662450, 22581653, 11823453, 32533946, 25904541, 30203441, 33131149, 29709244, 15028074, 22028457) (less)
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Pathogenic
(May 01, 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: SCV000545008.5
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg367 amino acid residue in SCN5A. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. 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: 11823453, 20129283). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 32533946) indicates that this missense variant is expected to disrupt SCN5A function. ClinVar contains an entry for this variant (Variation ID: 67633). This missense change has been observed in individuals with Brugada syndrome, primary electrical disease and unexplained cardiac arrest (PMID: 20129283, 21273195, 28341588, 28600387). This variant is present in population databases (rs199473097, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 367 of the SCN5A protein (p.Arg367Cys). (less)
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Likely pathogenic
(Feb 22, 2021)
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criteria provided, single submitter
Method: clinical testing
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Brugada syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV001653000.1
First in ClinVar: May 29, 2021 Last updated: May 29, 2021 |
Comment:
The p.Arg367Cys variant in SCN5A has been reported in at least 5 individuals affected with Brugada syndrome (BrS; Smits 2002 PMID:12106943, Amin 2011 PMID: 21273195, … (more)
The p.Arg367Cys variant in SCN5A has been reported in at least 5 individuals affected with Brugada syndrome (BrS; Smits 2002 PMID:12106943, Amin 2011 PMID: 21273195, Glazer 2020 PMID: 32533946, in at least 1 family with primary electrical disease (Proost 2017 PMID: 28341588), and in at least 2 individuals with unexplained cardiac arrest (Mellor 2017 PMID: 28600387, Meregalli 2009 PMID: 19251209). Additionally, it has been reported in 2 individuals with suspected BrS that were referred for genetic diagnostic testing (Kapplinger 2009 PMID: 19716085, Kapplinger 2010 PMID: 20129283) and by other clinical laboratories in ClinVar (Variation ID: 67633). This variant has also been identified in 0.006% (2/35330) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro patch clamp assays suggest that this variant results in a complete loss of sodium current (Meregalli 2009 PMID: 19251209, Glazer 2020 PMID: 32533946) and computational prediction tools and conservation analysis are consistent with pathogenicity. Another variant involving this codon (p.Arg367His) has been identified in individuals with disease and is classified as pathogenic by several clinical laboratories in ClinVar. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant SCN5-related disorder. ACMG/AMP Criteria applied: PM5_Supporting, PP3, PM2_Supporting, PS4_Moderate, PS3_Supporting. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Feb 05, 2022)
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criteria provided, single submitter
Method: clinical testing
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SCN5A-Related Disorders
Affected status: yes
Allele origin:
germline
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DASA
Accession: SCV002073757.1
First in ClinVar: Feb 10, 2022 Last updated: Feb 10, 2022 |
Comment:
The c.1099C>T;p.(Arg367Cys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 67633; PMID: 21273195; 20129283; 28600387) … (more)
The c.1099C>T;p.(Arg367Cys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 67633; PMID: 21273195; 20129283; 28600387) - PS4_moderate. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Ion_trans) - PM1. This variant is not present in population databases (rs199473097; gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (ClinVar ID: 9390 - c.1100G>A;p.(Arg367His)) - PM5. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is likely pathogenic. (less)
Number of individuals with the variant: 1
Sex: female
Geographic origin: Brazil
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Pathogenic
(Jan 23, 2024)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004803728.1
First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024 |
Comment:
Variant summary: SCN5A c.1099C>T (p.Arg367Cys) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Five … (more)
Variant summary: SCN5A c.1099C>T (p.Arg367Cys) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 248818 control chromosomes (gnomAD). c.1099C>T has been reported in the literature in multiple individuals affected with Brugada syndrome and Long QT syndrome (examples: Amin_2011, Meregalli_2009, Nannenberg_2012). Variant affecting the same amino acid has been classified as pathogenic in ClinVar (p.Arg367His CV ID 9390). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 19716085, 20129283, 22885917, 21273195, 19251209, 24136861, 22373669, 12106943). ClinVar contains an entry for this variant (Variation ID: 67633). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely Pathogenic
(Apr 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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Congenital long QT syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004824200.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
The c.1099C>T (p.Arg367Cys) variant in the SCN5A gene is located on the exon 9 and is predicted to replace arginine with cysteine at codon 367 … (more)
The c.1099C>T (p.Arg367Cys) variant in the SCN5A gene is located on the exon 9 and is predicted to replace arginine with cysteine at codon 367 (p.Arg367Cys). The variant has been reported in more than 10 unrelated individuals affected with Brugada syndrome or unexplained sudden cardiac arrest (PMID: 21273195, 20129283, 19251209, 22885917, 26538325, 28600387, 28341588). Negative functional impact of the variant was confirmed with the patch clamp experiment (PMID: 32533946, 19251209). This variant is rare in the general population according to gnomAD (3/280212). Computational prediction algorithms suggest a deleterious impact for this variant (REVEL score 0.956). Another variant disrupting the same amino acid (p.Arg367His) has been interpreted as pathogenic (ClinVar ID: 9390). Therefore, the c.1099C>T (p.Arg367Cys) variant of SCN5A has been classified as likely pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(Feb 01, 2024)
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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: SCV002732786.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.R367C pathogenic mutation (also known as c.1099C>T), located in coding exon 8 of the SCN5A gene, results from a C to T substitution at … (more)
The p.R367C pathogenic mutation (also known as c.1099C>T), located in coding exon 8 of the SCN5A gene, results from a C to T substitution at nucleotide position 1099. The arginine at codon 367 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the transmembrane-spanning DI-S5/S6 domain. This alteration has been identified in Brugada syndrome cohorts and is reported to co-segregate with disease (Smits JP et al. J. Am. Coll. Cardiol., 2002 Jul;40:350-6; Rodríguez-Mañero M et al. Heart Rhythm, 2016 Mar;13:669-82; Proost D et al. J Mol Diagn, 2017 Mar;pii:S1525-1578). This variant has also been described in a sudden cardiac arrest cohort (Mellor G et al. Circ Cardiovasc Genet, 2017 Jun;10:). This alteration is predicted to result in complete reduction of peak sodium channel current by patch-clamp analysis (Meregalli PG et al. Heart Rhythm, 2009 Mar;6:341-8). Alterations affecting the same amino acid (p.R367H, c.1100G>A and p.R367L, c.1100G>T) have been identified in Brugada syndrome cohorts; the p.R367H alteration has demonstrated absent sodium channel current in several in vitro studies and is reported to co-segregate with disease (Vatta M et al. Hum. Mol. Genet., 2002 Feb;11:337-45; Hong K et al. J. Cardiovasc. Electrophysiol., 2004 Jan;15:64-9; Takehara N et al. J. Intern. Med., 2004 Jan;255:137-42; Kapplinger JD et al. Heart Rhythm, 2010 Jan;7:33-46). This variant is also 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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not provided
(-)
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no classification provided
Method: literature only
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Congenital long QT syndrome
Affected status: unknown
Allele origin:
germline
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Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust
Accession: SCV000089909.3
First in ClinVar: Oct 22, 2013 Last updated: Oct 09, 2016 |
Comment:
This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19716085). This is a literature report, and does not necessarily … (more)
This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19716085). 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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High-Throughput Reclassification of SCN5A Variants. | Glazer AM | American journal of human genetics | 2020 | PMID: 32533946 |
Genetic Testing in the Evaluation of Unexplained Cardiac Arrest: From the CASPER (Cardiac Arrest Survivors With Preserved Ejection Fraction Registry). | Mellor G | Circulation. Cardiovascular genetics | 2017 | PMID: 28600387 |
Targeted Next-Generation Sequencing of 51 Genes Involved in Primary Electrical Disease. | Proost D | The Journal of molecular diagnostics : JMD | 2017 | PMID: 28341588 |
Monomorphic ventricular tachycardia in patients with Brugada syndrome: A multicenter retrospective study. | Rodríguez-Mañero M | Heart rhythm | 2016 | PMID: 26538325 |
Paralogue annotation identifies novel pathogenic variants in patients with Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia. | Walsh R | Journal of medical genetics | 2014 | PMID: 24136861 |
The diagnostic and therapeutic aspects of loss-of-function cardiac sodium channelopathies in children. | Chockalingam P | Heart rhythm | 2012 | PMID: 22885917 |
Paralogous annotation of disease-causing variants in long QT syndrome genes. | Ware JS | Human mutation | 2012 | PMID: 22581653 |
Mortality of inherited arrhythmia syndromes: insight into their natural history. | Nannenberg EA | Circulation. Cardiovascular genetics | 2012 | PMID: 22373669 |
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 |
Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test. | Kapplinger JD | Heart rhythm | 2009 | PMID: 19716085 |
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 |
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 |
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 |
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 rs199473097 ...
HelpRecord last updated May 08, 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.