ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.5126C>T (p.Ser1709Leu)
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.5126C>T (p.Ser1709Leu)
Variation ID: 9383 Accession: VCV000009383.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 38551243 (GRCh38) [ NCBI UCSC ] 3: 38592734 (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 Jul 5, 2015 Feb 28, 2024 Dec 30, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000335.5:c.5126C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000326.2:p.Ser1709Leu missense NM_001099404.2:c.5129C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001092874.1:p.Ser1710Leu missense NM_001099405.2:c.5075C>T NP_001092875.1:p.Ser1692Leu missense NM_001160160.2:c.5030C>T NP_001153632.1:p.Ser1677Leu missense NM_001160161.2:c.4967C>T NP_001153633.1:p.Ser1656Leu missense NM_001354701.2:c.5072C>T NP_001341630.1:p.Ser1691Leu missense NM_198056.3:c.5129C>T NP_932173.1:p.Ser1710Leu missense NC_000003.12:g.38551243G>A NC_000003.11:g.38592734G>A NG_008934.1:g.103430C>T LRG_289:g.103430C>T LRG_289t1:c.5129C>T LRG_289p1:p.Ser1710Leu LRG_289t3:c.5129C>T LRG_289p3:p.Ser1710Leu - Protein change
- S1710L, S1709L, S1656L, S1677L, S1691L, S1692L
- Other names
- p.S1710L:TCG>TTG
- p.Ser1710Leu
- Canonical SPDI
- NC_000003.12:38551242: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.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
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
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 |
3557 | - |
Conditions - Germline
Condition
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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
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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 (1) |
no assertion criteria provided
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Aug 11, 2000 | RCV000009981.12 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 17, 2017 | RCV000197520.10 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Dec 30, 2023 | RCV000183102.18 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 12, 2022 | RCV000246596.10 | |
not provided (1) |
no classification provided
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- | RCV000058743.11 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Dec 17, 2020 | RCV001841234.10 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 20, 2021 | RCV002504774.8 |
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
(Sep 10, 2013)
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criteria provided, single submitter
Method: clinical testing
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Brugada syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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UCLA Clinical Genomics Center, UCLA
Study: CES
Accession: SCV000255460.2 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Age: 20-29 years
Sex: female
Ethnicity/Population group: Hispanic
Testing laboratory: UCLA Clinical Genomics Center
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Likely pathogenic
(Jan 12, 2022)
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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: SCV000319116.6
First in ClinVar: Oct 02, 2016 Last updated: Nov 29, 2022 |
Comment:
The p.S1710L variant (also known as c.5129C>T) is located in coding exon 27 of the SCN5A gene. This alteration results from a C to T … (more)
The p.S1710L variant (also known as c.5129C>T) is located in coding exon 27 of the SCN5A gene. This alteration results from a C to T substitution at nucleotide position 5129. The serine at codon 1710 is replaced by leucine, an amino acid with dissimilar properties. This variant has been reported in individuals with Brugada syndrome (Shin DJ et al. Life Sci, 2007 Jan;80:716-24; Millat G et al. Clin Biochem, 2009 Apr;42:491-9; Lee H et al. JAMA, 2014 Nov;312:1880-7; Ciconte G et al. Eur Heart J, 2021 03;42:1082-1090). This variant has also been detected in individuals with other SCN5A-related arrhythmias, including idiopathic ventricular fibrillation (IVF), progressive family heart block, and sick sinus syndrome (Akai J et al. FEBS Lett, 2000 Aug;479:29-34; Makita N et al. Circ Arrhythm Electrophysiol, 2012 Feb;5:163-72; Lee YS et al. Korean Circ J, 2016 Jan;46:63-71). Limited functional studies in human kidney cells have demonstrated that the alteration affected the duration of activation and inactivation of the protein (Akai J et al FEBS Lett. 2000;479(1-2):29-34 and Sharai N et al. Cardiovasc Res. 2002;53(2):348-354). 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 majority of available evidence to date, this variant is likely to be pathogenic. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Sep 20, 2021)
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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: SCV002798744.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Likely pathogenic
(Oct 11, 2022)
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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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004226747.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP3, PM1, PS3_moderate, PS4_moderate
Number of individuals with the variant: 1
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Pathogenic
(Nov 17, 2017)
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criteria provided, single submitter
Method: clinical testing
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BRUGADA SYNDROME 1
Affected status: yes
Allele origin:
germline
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Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV000996083.1
First in ClinVar: Oct 20, 2019 Last updated: Oct 20, 2019 |
Comment:
This variant has been previously reported in a patient with clinically diagnosed Brugada Syndrome (PMID: 10940383). Multiple clinical labs have also classified the variant as … (more)
This variant has been previously reported in a patient with clinically diagnosed Brugada Syndrome (PMID: 10940383). Multiple clinical labs have also classified the variant as pathogenic or likely pathogenic. Functional studies demonstrate that p.Ser1710Leu channels have abnormal biophysical properties, which may result in fast inactivation dysfunction of the sodium channel (PMID: 10940383, 11827685). Ser1710Leu is located in the highly conserved pore-forming linker between segments 5 and 6 in transmembrane domain 4. Ser1710Leu results in a non-conservative amino acid substitution of a polar serine with a non-polar leucine at a position that is highly conserved across species. There are four reports of this variant in gnomAD, thus it is presumed to be rare. Based on the available evidence, the variant is classified as pathogenic. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Dec 17, 2020)
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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: SCV001349526.2
First in ClinVar: Jun 22, 2020 Last updated: Jun 19, 2021 |
Comment:
This missense variant replaces serine with leucine at codon 1710 in the transmembrane domain DIV of the SCN5A protein. Computational prediction suggests that this variant … (more)
This missense variant replaces serine with leucine at codon 1710 in the transmembrane domain DIV 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). A functional study has shown that this variant causes alterations in channel activation and inactivation properties (PMID: 10940383). This variant has been reported in three individuals affected with Brugada syndrome (PMID: 14961552, 17141278, 19026623) and in an individual suspected of having Brugada syndrome (PMID: 25326637) in the literature. External laboratories have reported multiple carriers of this variant affected with Brugada syndrome (Clinvar SCV000235512.11, SCV000280476.1). This variant has also been observed in individuals affected with idiopathic ventricular fibrillation (PMID: 10940383), progressive familial heart block type I and idiopathic ventricular fibrillation (PMID: 22247482), paroxysmal familial ventricular fibrillation (PMID:23139254) and sick sinus syndrome (PMID: 26798387). This variant has been identified in 4/246266 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic. (less)
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Pathogenic
(Oct 24, 2022)
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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: SCV000235512.14
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect by causing a negative shift in the voltage-dependence of fast inactivation and slower recovery from fast inactivation compared … (more)
Published functional studies demonstrate a damaging effect by causing a negative shift in the voltage-dependence of fast inactivation and slower recovery from fast inactivation compared to wildtype (Akai et al., 2000); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 14961552, 17141278, 10940383, 22247482, 26798387, 25326637, 23139254, 30975432, 11827685, 17698727, 28150151, 19026623, 32091595, 30609406, 29625023, 28152038, 32553838, 34649698, 33221895) (less)
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Pathogenic
(Dec 30, 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: SCV000637172.5
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1710 of the SCN5A protein (p.Ser1710Leu). … (more)
This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1710 of the SCN5A protein (p.Ser1710Leu). This variant is present in population databases (rs137854604, gnomAD 0.009%). This missense change has been observed in individuals with Brugada syndrome, idiopathic ventricular fibrillation, progressive familial heart block type I, sick sinus syndrome and paroxysmal familial ventricular fibrillation (PMID: 10940383, 14961552, 19026623, 22247482, 23139254, 25326637, 26798387). ClinVar contains an entry for this variant (Variation ID: 9383). 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: 10940383). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Jan 14, 2014)
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no assertion criteria provided
Method: clinical testing
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Not provided
Affected status: not provided
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000280476.1
First in ClinVar: Jul 05, 2015 Last updated: Jul 05, 2015 |
Comment:
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case … (more)
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Ser1710Leu (S1710L; c.5129 C>T) in the SCN5A gene This variant has been previously observed in five unrelated cases of Brugada syndrome (including one case of idiopathic VF without a strict Brugada diagnosis). No published segregation data is available, but good in-vitro functional data is available. With our 2 cases (both have Mexican ancestry), this makes 7 families. Akai et al. (2000) first reported the variant in a Japanese patient with idiopathic ventricular fibrillation, a history of recurrent syncope, and sudden death in a paternal uncle and paternal grandfather, but no type 1 Brugada pattern on EKG. Shin et al. (2007) reported the variant in a male Korean patient with a type 1 Brugada syndrome pattern on EKG that was unmasked by flecainide and a family history of sudden cardiac death. The testing laboratory reports that Ser1710Leu has also been seen in three additional unrelated individuals tested for Brugada syndrome at their lab (as of January 2014). Functional data is available. The SCN5A gene produces the cardiac sodium channel alpha subunit, and Ser1710 is located in the highly conserved pore-forming linker between segments 5 and 6 in transmembrane domain 4 (Akai et al. 2000; Shin et al. 2007). Functional studies show that Ser1710Leu mutant channels have altered biophysical properties, which may result in diminished sodium current into the myocyte. Akai et al. (2000) and Shirai et al. (2002) showed that mutant channels expressed in human embryonic kidney cells show faster inactivation and current decay, a large hyperpolarizing shift in the voltage-dependent threshold for steady-state inactivation, a positive shift in the voltage-dependent threshold for channel activation, and delayed recovery from inactivation. Variants at nearby residues (within 10 amino acids to either side) have been associated with Brugada syndrome, suggesting the functional importance of this region of the protein. These include Thr1709Arg, Thr1709Met, Thr1709del, Gly1712Ser, Asp1714Gly (inherited arrhythmias database: Molecular Cardiology Laboratories of IRCCS Fondazione Salvatore Maugeri; GeneDx report of HGMD variants). Ser1710Leu is a nonconservative amino acid change from a polar Serine to a nonpolar Leucine. The Serine at codon 1710 is completely conserved across 39 vertebrate species examined. Surrounding residues are also very highly conserved. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be "probably damaging" (with a maximum score of 1). In total the variant has not been seen in ~6850 individuals from published reports and publicly available population datasets. There is no variation at residue 1710 listed in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals. There is also no variation at this residue listed in dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP) or 1000 genomes (http://browser.1000genomes.org/index.htm) as of June 27, 2012. The variant was not observed in published controls: Akai et al. (2000) did not find Ser1710Leu in 150 (Japanese?) controls. Shin et al. (2007) did not detect it in 200 Korean controls. GeneDx did not report controls. (less)
Number of individuals with the variant: 7
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Pathogenic
(Aug 11, 2000)
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no assertion criteria provided
Method: literature only
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VENTRICULAR FIBRILLATION, PAROXYSMAL FAMILIAL, 1 (1 patient)
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000030202.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 08, 2017 |
Comment on evidence:
Akai et al. (2000) screened 25 Japanese patients with idiopathic ventricular fibrillation (VF1; 603829). The diagnosis was based on the occurrence of at least one … (more)
Akai et al. (2000) screened 25 Japanese patients with idiopathic ventricular fibrillation (VF1; 603829). The diagnosis was based on the occurrence of at least one episode of syncope and/or cardiac arrest and documentation of ventricular fibrillation. Structural heart disorders were excluded. Eighteen patients were diagnosed as Brugada syndrome. The authors identified a heterozygous ser1710-to-leu missense mutation of the SCN5A gene in a 39-year-old man who was admitted to the hospital for recurrent syncope and suffered an episode of spontaneous ventricular fibrillation while hospitalized. An implanted cardiac defibrillator was successful in preventing further attacks of palpitation or syncope. Brugada syndrome was not present. The paternal grandfather and a paternal uncle had died suddenly in their sixth decade of unknown cause; the parents and sibs were asymptomatic. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Ventricular fibrillation
Affected status: unknown
Allele origin:
germline
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Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust
Accession: SCV000090263.3
First in ClinVar: Oct 22, 2013 Last updated: Oct 09, 2016 |
Comment:
This variant has been reported as associated with Ventricular Fibrillation, idiopathic in the following publications (PMID:10940383;PMID:11827685;PMID:17141278;PMID:22247482). This is a literature report, and does not necessarily … (more)
This variant has been reported as associated with Ventricular Fibrillation, idiopathic in the following publications (PMID:10940383;PMID:11827685;PMID:17141278;PMID:22247482). 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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Distinct Features of Probands With Early Repolarization and Brugada Syndromes Carrying SCN5A Pathogenic Variants. | Zhang ZH | Journal of the American College of Cardiology | 2021 | PMID: 34649698 |
Brugada syndrome genetics is associated with phenotype severity. | Ciconte G | European heart journal | 2021 | PMID: 33221895 |
The Impact of Rapid Exome Sequencing on Medical Management of Critically Ill Children. | Freed AS | The Journal of pediatrics | 2020 | PMID: 32553838 |
Using High-Resolution Variant Frequencies Empowers Clinical Genome Interpretation and Enables Investigation of Genetic Architecture. | Whiffin N | American journal of human genetics | 2019 | PMID: 30609406 |
Exome sequencing covers >98% of mutations identified on targeted next generation sequencing panels. | LaDuca H | PloS one | 2017 | PMID: 28152038 |
Genetic Variation of SCN5A in Korean Patients with Sick Sinus Syndrome. | Lee YS | Korean circulation journal | 2016 | PMID: 26798387 |
Clinical exome sequencing for genetic identification of rare Mendelian disorders. | Lee H | JAMA | 2014 | PMID: 25326637 |
Non optical semi-conductor next generation sequencing of the main cardiac QT-interval duration genes in pooled DNA samples. | Gómez J | Journal of cardiovascular translational research | 2014 | PMID: 24190697 |
Integration of genetics into a systems model of electrocardiographic traits using HumanCVD BeadChip. | Gaunt TR | Circulation. Cardiovascular genetics | 2012 | PMID: 23139254 |
A connexin40 mutation associated with a malignant variant of progressive familial heart block type I. | Makita N | Circulation. Arrhythmia and electrophysiology | 2012 | PMID: 22247482 |
Rapid, sensitive and inexpensive detection of SCN5A genetic variations by high resolution melting analysis. | Millat G | Clinical biochemistry | 2009 | PMID: 19026623 |
A novel mutation in the SCN5A gene is associated with Brugada syndrome. | Shin DJ | Life sciences | 2007 | PMID: 17141278 |
Unexpected mexiletine responses of a mutant cardiac Na+ channel implicate the selectivity filter as a structural determinant of antiarrhythmic drug access. | Sasaki K | Molecular pharmacology | 2004 | PMID: 15266024 |
Sodium channel gene (SCN5A) mutations in 44 index patients with Brugada syndrome: different incidences in familial and sporadic disease. | Schulze-Bahr E | Human mutation | 2003 | PMID: 14961552 |
A mutant cardiac sodium channel with multiple biophysical defects associated with overlapping clinical features of Brugada syndrome and cardiac conduction disease. | Shirai N | Cardiovascular research | 2002 | PMID: 11827685 |
A novel SCN5A mutation associated with idiopathic ventricular fibrillation without typical ECG findings of Brugada syndrome. | Akai J | FEBS letters | 2000 | PMID: 10940383 |
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Text-mined citations for rs137854604 ...
HelpRecord last updated Apr 15, 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.