ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.3389C>T (p.Thr1130Ile)
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.3389C>T (p.Thr1130Ile)
Variation ID: 67795 Accession: VCV000067795.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 38576780 (GRCh38) [ NCBI UCSC ] 3: 38618271 (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 Jan 25, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000335.5:c.3389C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000326.2:p.Thr1130Ile missense NM_001099404.2:c.3392C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001092874.1:p.Thr1131Ile missense NM_001099405.2:c.3392C>T NP_001092875.1:p.Thr1131Ile missense NM_001160160.2:c.3389C>T NP_001153632.1:p.Thr1130Ile missense NM_001160161.2:c.3230C>T NP_001153633.1:p.Thr1077Ile missense NM_001354701.2:c.3389C>T NP_001341630.1:p.Thr1130Ile missense NM_198056.3:c.3392C>T NP_932173.1:p.Thr1131Ile missense NC_000003.12:g.38576780G>A NC_000003.11:g.38618271G>A NG_008934.1:g.77893C>T LRG_289:g.77893C>T LRG_289t1:c.3392C>T LRG_289p1:p.Thr1131Ile Q14524:p.Thr1131Ile - Protein change
- T1130I, T1131I, T1077I
- Other names
- p.T1131I:ACC>ATC
- Canonical SPDI
- NC_000003.12:38576779: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.
The Genome Aggregation Database (gnomAD), exomes 0.00003
Exome Aggregation Consortium (ExAC) 0.00004
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00010
1000 Genomes Project 30x 0.00031
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 |
3773 | 4212 |
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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not provided (1) |
no classification provided
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- | RCV000058569.11 | |
Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
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Jan 25, 2024 | RCV000587127.13 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 2, 2023 | RCV002453376.10 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 22, 2021 | RCV002498344.8 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Dec 1, 2023 | RCV001842336.13 |
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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Uncertain significance
(Jul 02, 2017)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000700032.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The c.3392C>T (p.Thr1131Ile) in SCN5A gene is a missense change that involves a non-conserved nucleotide resulting in a non-conservative amino acid substitution located … (more)
Variant summary: The c.3392C>T (p.Thr1131Ile) in SCN5A gene is a missense change that involves a non-conserved nucleotide resulting in a non-conservative amino acid substitution located within the cytoplasmic loop between domains II-III. 4/5 in silico tools predict benign, although at least one functional study have shown deleterious effect on the protein function, suggesting a potential causative reason for atrial fibrillation (AF) (Wang, 2010). However, this study has yet to be published in peer-reviewed journal at this time of this review therefore the evidence cannot be unequivocally considered. The variant is present in the large control population dataset of ExAC at a frequency of 4.455e-05 (4/89792 chrs tested), predominantly in individuals of African descent (0.000417; 3/7194 chrs tested). The variant has also been identified in gnomAD dataset at similar frequencies (0.00003; 8/267102 chrs tested). The observed frequency in African cohort exceeds the maximal expected frequency of a pathogenic allele (0.00016) in this gene. However, since no clinical information on ExAC participants are available, the possibility of them being a silent carrier of deleterious variant cannot be ruled out. In addition, the variant was reported in two patients presented with AF and SIDS. Both cases were reported to be of African descent. Since no segregation analysis was done for these patients, there are not enough evidence to classify this variant with confidence. Lastly, the c.3392C>T is cites as VUS by several reputable databases/clinical laboratories. Taking all line of evidence into consideration, the variant was classified as VUS until more information becomes available. (less)
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Uncertain significance
(Jul 22, 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: SCV002776791.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Jul 25, 2019)
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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: SCV000235441.12
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
Identified in individuals referred for cardiac genetic testing at GeneDx; however, at least one of these probands harbored a pathogenic variant in another cardiac disease-related … (more)
Identified in individuals referred for cardiac genetic testing at GeneDx; however, at least one of these probands harbored a pathogenic variant in another cardiac disease-related gene; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 67795; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29247119, 18378609, 21143119, 25175087, 24631775, 28316956, 25904541) (less)
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Uncertain significance
(Mar 28, 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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV004564494.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
The SCN5A c.3392C>T; p.Thr1131Ile variant (rs199473197) is reported in an individual with atrial fibrillation (Darbar 2008) and in a cohort of sudden unexplained deaths (Lin … (more)
The SCN5A c.3392C>T; p.Thr1131Ile variant (rs199473197) is reported in an individual with atrial fibrillation (Darbar 2008) and in a cohort of sudden unexplained deaths (Lin 2017). This variant is also reported in ClinVar (Variation ID: 67795). It is found on eight alleles in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.345). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Darbar D et al. Cardiac sodium channel (SCN5A) variants associated with atrial fibrillation. Circulation. 2008 Apr 15;117(15):1927-35. PMID: 18378609. Lin Y et al. Applying High-Resolution Variant Classification to Cardiac Arrhythmogenic Gene Testing in a Demographically Diverse Cohort of Sudden Unexplained Deaths. Circ Cardiovasc Genet. 2017 Dec;10(6):e001839. PMID: 29247119. (less)
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Uncertain Significance
(Dec 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiac arrhythmia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004815016.1
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:
This missense variant replaces threonine with isoleucine at codon 1131 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces threonine with isoleucine at codon 1131 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). An in vitro functional study has shown that this variant affects the voltage-dependence of channel activation (Wang et al., 2010). This variant has been reported in an individual affected with atrial fibrillation (AF) who has a family history of AF, with both parents and two children affected (PMID: 18378609), and in another individual with sudden unexplained death (PMID: 24631775). This variant has been identified in 8/270004 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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)
Number of individuals with the variant: 5
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Uncertain significance
(Dec 06, 2022)
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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: SCV001356413.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces threonine with isoleucine at codon 1131 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces threonine with isoleucine at codon 1131 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). An in vitro functional study has shown that this variant affects the voltage-dependence of channel activation (Wang et al., 2010). This variant has been reported in an individual affected with atrial fibrillation (AF) who has a family history of AF, with both parents and two children affected (PMID: 18378609), and in another individual with sudden unexplained death (PMID: 24631775). This variant has been identified in 8/270004 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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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Uncertain significance
(Jan 25, 2024)
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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: SCV000545083.6
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1131 of the SCN5A protein (p.Thr1131Ile). … (more)
This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1131 of the SCN5A protein (p.Thr1131Ile). This variant is present in population databases (rs199473197, gnomAD 0.02%). This missense change has been observed in individual(s) with atrial fibrillation (PMID: 18378609, 24631775). ClinVar contains an entry for this variant (Variation ID: 67795). 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 tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Jun 02, 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: SCV002618318.3
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.T1131I variant (also known as c.3392C>T), located in coding exon 18 of the SCN5A gene, results from a C to T substitution at nucleotide … (more)
The p.T1131I variant (also known as c.3392C>T), located in coding exon 18 of the SCN5A gene, results from a C to T substitution at nucleotide position 3392. The threonine at codon 1131 is replaced by isoleucine, an amino acid with similar properties, and is located in the DII/DIII interdomain linker region of the protein. This variant has been detected in an individual with atrial fibrillation, bradycardia, and congestive heart failure, and has been detected in a sudden infant death case (Darbar D et al. Circulation, 2008 Apr;117:1927-35; Wang D et al. Forensic Sci. Int., 2014 Apr;237:90-9). This variant has also been detected in a control cohort; however, details were limited (Kapplinger JD et al. Circ Cardiovasc Genet. 2015 Aug;8(4):582-95). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Atrial fibrillation
Affected status: unknown
Allele origin:
germline
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Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust
Accession: SCV000090089.3
First in ClinVar: Oct 22, 2013 Last updated: Oct 09, 2016 |
Comment:
This variant has been reported as associated with Atrial fibrillation in the following publications (PMID:18378609). This is a literature report, and does not necessarily reflect … (more)
This variant has been reported as associated with Atrial fibrillation in the following publications (PMID:18378609). 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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Applying High-Resolution Variant Classification to Cardiac Arrhythmogenic Gene Testing in a Demographically Diverse Cohort of Sudden Unexplained Deaths. | Lin Y | Circulation. Cardiovascular genetics | 2017 | PMID: 29247119 |
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 |
Cardiac channelopathy testing in 274 ethnically diverse sudden unexplained deaths. | Wang D | Forensic science international | 2014 | PMID: 24631775 |
Voltage-gated sodium channels: mutations, channelopathies and targets. | Andavan GS | Current medicinal chemistry | 2011 | PMID: 21143119 |
Cardiac sodium channel (SCN5A) variants associated with atrial fibrillation. | Darbar D | Circulation | 2008 | PMID: 18378609 |
Text-mined citations for rs199473197 ...
HelpRecord last updated Sep 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.