The p.Thr1304Met variant in SCN5A has been reported in 3 individuals with long Q T syndrome, 1 infant with sudden infant death syndrome, 1 individual with Brugad a syndrome, 1 individual with early-onset atrial fibrillation (Wattanasirichaigo on 1999, Priori 2000, Splawski 2000, Arnestad 2007, Olesen 2012, Kim 2014). This variant segregated with LQTS in 2 affected relatives from 1 family and with Br ugada syndrome in 1 affected relative from 1 family. However, other clinical lab oratories have observed this variant in individuals who carried other disease-ca using variants (GeneDx, Emory, Invitae; personal communication) and this variant has been reported in multiple healthy individuals (Weeke 2015, Kapplinger 2015) . Additionally, it is unclear if the same variant would be causative for such a diverse set of phenotypes, suggesting that it may not have a functional effect. This variant has also been identified in 0.03% (35/126116) of European chromosom es by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs199473603). Additionally, in vitro functional studies have shown confli cting results (Want 2007, Makita 2008, Beyder 2014). In summary, due to the pres ence of conflicting data, the clinical significance of the p.Thr1304Met variant is uncertain. ACMG/AMP Criteria applied: PP1; BP5.
ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.3908C>T (p.Thr1303Met)
Germline
Classification
Help
criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.
Conflicting classifications of pathogenicity
Uncertain significance(17); Likely benign(1)
Uncertain significance(17); Likely benign(1)
18 out of 26 submissions contributed to this classification
Help
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.
25
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000335.5(SCN5A):c.3908C>T (p.Thr1303Met)
Variation ID: 67835 Accession: VCV000067835.72
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3p22.2 3: 38562467 (GRCh38) [ NCBI UCSC ] 3: 38603958 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Dec 6, 2014 Jan 11, 2026 Oct 21, 2025 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000335.5:c.3908C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000326.2:p.Thr1303Met missense NM_001099404.2:c.3911C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001092874.1:p.Thr1304Met missense NM_001099405.2:c.3911C>T NP_001092875.1:p.Thr1304Met missense NM_001160160.2:c.3908C>T NP_001153632.1:p.Thr1303Met missense NM_001160161.2:c.3749C>T NP_001153633.1:p.Thr1250Met missense NM_001354701.2:c.3908C>T NP_001341630.1:p.Thr1303Met missense NM_198056.3:c.3911C>T NP_932173.1:p.Thr1304Met missense NC_000003.12:g.38562467G>A NC_000003.11:g.38603958G>A NG_008934.1:g.92206C>T LRG_289:g.92206C>T LRG_289t1:c.3911C>T LRG_289p1:p.Thr1304Met LRG_289t2:c.3908C>T LRG_289p2:p.Thr1303Met LRG_289t3:c.3911C>T LRG_289p3:p.Thr1304Met - Protein change
- T1303M, T1304M, T1250M
- Other names
-
p.T1304M:ACG>ATG
Thr1304Met
- Canonical SPDI
- NC_000003.12:38562466:G:A
-
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.
-
0.00020 (A)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
1000 Genomes Project 30x 0.00016
The Genome Aggregation Database (gnomAD), exomes 0.00018
1000 Genomes Project 0.00020
The Genome Aggregation Database (gnomAD) 0.00021
Exome Aggregation Consortium (ExAC) 0.00022
The Genome Aggregation Database (gnomAD) 0.00022
Trans-Omics for Precision Medicine (TOPMed) 0.00026
The Genome Aggregation Database (gnomAD), exomes 0.00035
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00040
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| SCN5A | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
4328 | 4823 | |
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. |
|---|---|---|---|---|
| not provided (1) |
no classification provided
|
- | RCV000058613.11 | |
| no classifications from unflagged records (1) |
no classifications from unflagged records
|
Dec 7, 2023 | RCV000148846.12 | |
| Uncertain significance (3) |
criteria provided, single submitter
|
Jan 4, 2024 | RCV000496069.16 | |
| no classifications from unflagged records (1) |
no classifications from unflagged records
|
Dec 7, 2023 | RCV000470787.21 | |
| Uncertain significance (7) |
criteria provided, multiple submitters, no conflicts
|
Oct 21, 2025 | RCV000725469.42 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Jul 24, 2025 | RCV000618218.15 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Jan 17, 2020 | RCV000993797.10 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Apr 29, 2025 | RCV000824759.17 | |
| Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
|
Dec 10, 2024 | RCV000987206.14 | |
| Likely benign (1) |
criteria provided, single submitter
|
Feb 18, 2025 | RCV001842354.12 | |
|
SCN5A-related disorder
|
Uncertain significance (2) |
criteria provided, single submitter
|
- | RCV004537261.4 |
| click to load more conditions click to collapse | ||||
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. |
Expand all rows
Collapse all rows
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Apr 26, 2018)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not specified |
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000710929.2
First in ClinVar: Apr 09, 2018 Last updated: Aug 26, 2019 |
Comment:
show
The p.Thr1304Met variant in SCN5A has been reported in 3 individuals with long Q T syndrome, 1 infant with sudden infant death syndrome, 1 individual with Brugad a syndrome, 1 individual with early-onset atrial fibrillation (Wattanasirichaigo on 1999, Priori 2000, Splawski 2000, Arnestad 2007, Olesen 2012, Kim 2014). This variant segregated with LQTS in 2 affected relatives from 1 family and with Br ugada syndrome in 1 affected relative from 1 family. However, other clinical lab oratories have observed this variant in individuals who carried other disease-ca using variants (GeneDx, Emory, Invitae; personal communication) and this variant has been reported in multiple healthy individuals (Weeke 2015, Kapplinger 2015) . Additionally, it is unclear if the same variant would be causative for such a diverse set of phenotypes, suggesting that it may not have a functional effect. This variant has also been identified in 0.03% (35/126116) of European chromosom es by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs199473603). Additionally, in vitro functional studies have shown confli cting results (Want 2007, Makita 2008, Beyder 2014). In summary, due to the pres ence of conflicting data, the clinical significance of the p.Thr1304Met variant is uncertain. ACMG/AMP Criteria applied: PP1; BP5. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: not provided
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: not provided
Number of individuals with the variant: 8
|
|
|
Uncertain significance
(May 28, 2019)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Brugada syndrome 1 |
Mendelics
Accession: SCV001136455.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Uncertain significance
(May 14, 2020)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Brugada syndrome 1 |
Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV001425372.1
First in ClinVar: Aug 01, 2020 Last updated: Aug 01, 2020 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Uncertain significance
(Feb 18, 2020)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001160606.2
First in ClinVar: Feb 10, 2020 Last updated: Jan 26, 2021 |
Comment:
show
The SCN5A c.3911C>T; p.Thr1304Met variant (rs199473603) is reported in the literature in individuals affected with long QT syndrome (Kapa 2009, Wattanasirichaigoon 1999) or Brugada syndrome (Kim 2014), which have different mechanisms of pathogenicity. This variant is also reported with conflicting interpretations by multiple laboratories in ClinVar (Variation ID: 67835), and is found in the non-Finnish European population with an allele frequency of 0.031% (40/127748 alleles) in the Genome Aggregation Database. The threonine at codon 1304 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, functional analyses of the variant protein show conflicting effects on channel function (Beyder 2014, Wang 2007). Due to conflicting information, the clinical significance of the p.Thr1304Met variant is uncertain at this time. References: Beyder A et al. Loss-of-function of the voltage-gated sodium channel NaV1.5 (channelopathies) in patients with irritable bowel syndrome. Gastroenterology. 2014 Jun;146(7):1659-1668. Kapa S et al. Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants. Circulation. 2009 Nov 3;120(18):1752-60. Kim G et al. A pediatric case of Brugada syndrome diagnosed by fever-provoked ventricular tachycardia. Korean J Pediatr. 2014 Aug;57(8):374-8. Wang DW et al. Cardiac sodium channel dysfunction in sudden infant death syndrome. Circulation. 2007 Jan 23;115(3):368-76. Wattanasirichaigoon D et al. Sodium channel abnormalities are infrequent in patients with long QT syndrome: identification of two novel SCN5A mutations. Am J Med Genet. 1999 Oct 29;86(5):470-6. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Uncertain significance
(Apr 20, 2018)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Brugada syndrome 1 |
Baylor Genetics
Accession: SCV001527656.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
show
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. (less)
Observation: 1
Collection method: clinical testing
Allele origin: maternal
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: maternal
Affected status: yes
|
|
|
Uncertain significance
(Jan 04, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Long QT syndrome 3 |
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: CSER-HudsonAlpha
Accession: SCV000584112.2 First in ClinVar: Jul 30, 2017 Last updated: Jan 26, 2024 |
Observation:
2
Observation 1
Collection method: research
Allele origin: unknown
Affected status: unknown
Number of individuals with the variant: 1
Observation 2
Collection method: research
Allele origin: maternal
Affected status: unknown
Number of individuals with the variant: 1
|
|
|
Uncertain significance
(Jan 30, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000545009.10
First in ClinVar: Apr 17, 2017 Last updated: Feb 16, 2025 |
Comment:
show
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1304 of the SCN5A protein (p.Thr1304Met). This variant is present in population databases (rs199473603, gnomAD 0.03%). This missense change has been observed in individual(s) with SCN5A-related conditions (PMID: 10508990, 17210839, 17210841, 19716085, 19841300, 24631775, 25210526, 28341588, 30847666). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 67835). 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: 17210841). 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)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Uncertain significance
(Dec 10, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Brugada syndrome 1
(Autosomal dominant inheritance)
|
Medical Genetics Clinic, University of Catania
Accession: SCV005689474.2
First in ClinVar: Mar 11, 2025 Last updated: Apr 13, 2025 |
Comment:
show
The SCN5A c.3911C>T variant (rs199473603) is present in population databases (gnomAD 0.03%). Computational prediction analyses (Polyphen-2, SIFT) suggest that this variant has deleterious effect on protein structure and function. Functional studies have shown conflicting results in channel function (PMID: 17210841, 24613995). This variant was reported in individuals with long QT syndrome (PMID: 17210839, 19716085, 19841300); Brugada syndrome (PMID: 34461752, 25210526), sudden unexplained death (PMID: 17210839, 17210841, 24631775, 32652122). Based on conflicting evidence, the clinical role of SCN5A c.3911C>T variant cannot be determined. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
Clinical Features:
HPO: 0001638: Cardiomyopathy (present) , HPO: 0001639: Hypertrophic cardiomyopathy (present) , HPO: 0011675: Arrhythmia (present)
Comment on clinical features:
In 2022, during a correction surgery for gynecomastia, the patient suffered cardiac arrest treated with CPR, adrenaline and defibrillation. On the coronary angiography, coronary arteries were free from angiographically significant lesions. On the ECG, there were sinus bradycardia, right intraventricular conduction delay, ventricular repolarization disorders with antero-septal location. The findings on cardiac MRI initially appear to be attributable to a hypertrophic phenotype with mapping alterations and initial disarray as per the form of hypertrophic cardiomyopathy picture with Brugada phenocopy. A defibrillator was implanted in 2022. NGS panel for hypertrophic cardiomyopathy was performed, giving normal results. NGS panel was subsequently performed for suspected arrhythmogenic cardiomyopathy/Brugada syndrome.
Indication for testing: Suspected arrhythmogenic cardiomyopathy/Brugada Syndrome
Zygosity: Single Heterozygote
Age: 20-29 years
Sex: male
Ethnicity/Population group: Caucasian
Geographic origin: Sicily
|
|
|
Uncertain significance
(Dec 11, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Cardiovascular phenotype |
Ambry Genetics
Accession: SCV000736754.6
First in ClinVar: Apr 14, 2018 Last updated: Apr 28, 2025 |
Comment:
show
The p.T1304M variant (also known as c.3911C>T), located in coding exon 21 of the SCN5A gene, results from a C to T substitution at nucleotide position 3911. The threonine at codon 1304 is replaced by methionine, an amino acid with similar properties, and is located in the transmembrane DIII-S4 region. This alteration has been reported in association with long QT syndrome (Wattanasirichaigoon D et al. Am. J. Med. Genet., 1999 Oct;86:470-6; Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303). In one family, alteration carriers showed variable clinical and electrophysiological phenotypes with several having borderline findings (Wattanasirichaigoon D et al. Am. J. Med. Genet., 1999 Oct;86:470-6). This alteration was also detected in individuals with a transient Brugada pattern, lone atrial fibrillation, or sudden infant death syndrome (Wang DW et al. Circulation, 2007 Jan;115:368-76; Olesen MS et al. Circ Cardiovasc Genet, 2012 Aug;5:450-9; Wang D et al. Forensic Sci. Int., 2014 Apr;237:90-9; Kim G et al. Korean J Pediatr, 2014 Aug;57:374-8). In addition, this alteration was reported in hypertrophic cardiomyopathy, dilated cardiomyopathy cohorts as well as exome sequencing and cohorts not selected for the presence of cardiovascular disease; however, limited clinical information was provided (Andreasen C et al. Can J Cardio. 2013;29(9):1104-9; Dorschner MO et al. Am J Hum Genet. 2013;93(4):631-40; Lopes LR et al. Heart, 2015 Feb;101:294-301; Amendola LM et al. Genome Res., 2015 Mar;25:305-15; Van Driest SL et al. JAMA, 2016 Jan;315:47-57; Gigli M et al. J Am Coll Cardiol. 2019 09;74(11):1480-1490; Diebold I et al. Hum Mutat. 2020 05;41(5):1025-1032). While some research groups reported that this alteration would lead to gain of function effects (Wang DW et al. Circulation, 2007 Jan;115:368-76; Arnestad M et al. Circulation, 2007 Jan;115:361-7), others found no significant difference between mutant and wild type channel function (Beyder A et al. Gastroenterology, 2014 Jun;146:1659-1668; Makita N et al. J. Clin. Invest., 2008 Jun;118:2219-29); however, the experimental systems were not the same and the physiological significance of these results is unclear. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Likely benign
(Feb 18, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Cardiac arrhythmia |
Color Diagnostics, LLC DBA Color Health
Accession: SCV000913703.6
First in ClinVar: May 20, 2019 Last updated: May 03, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Platform type: NGS
|
|
|
Uncertain significance
(Apr 29, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not specified |
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005185790.3
First in ClinVar: Aug 11, 2024 Last updated: Jun 14, 2025 |
Comment:
show
Variant summary: SCN5A c.3911C>T (p.Thr1304Met) 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 0.00018 in 247644 control chromosomes. The observed variant frequency is approximately 8.53 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Long QT Syndrome phenotype (2.1e-05). c.3911C>T has been reported in the literature in individuals affected with Long QT Syndrome and other related conditions (e.g. Wattanasirichaigoon_1999, Arnestad_2007, Kapplinger_2009, Kapa_2009, van Lint_2019). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and demonstrates an affect on protein function (Wang_2007). The following publications have been ascertained in the context of this evaluation (PMID: 17210839, 37937776, 35534676, 19841300, 19716085, 36396199, 17210841, 10508990, 39486665, 36129056, 30847666). ClinVar contains an entry for this variant (Variation ID: 67835). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Uncertain significance
(Jul 24, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Cardiovascular phenotype |
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV006309874.1
First in ClinVar: Aug 30, 2025 Last updated: Aug 30, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Uncertain significance
(Oct 21, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Not provided |
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV007137234.1
First in ClinVar: Jan 11, 2026 Last updated: Jan 11, 2026 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Number of individuals with the variant: 1
|
|
|
Uncertain significance
(Nov 16, 2015)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Eurofins Ntd Llc (ga)
Accession: SCV000337160.5
First in ClinVar: Dec 06, 2016 Last updated: Apr 13, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Number of individuals with the variant: 1
Zygosity: Single Heterozygote
Sex: mixed
|
|
|
Uncertain significance
(Jan 17, 2020)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Conduction disorder of the heart
(Autosomal dominant inheritance)
|
Robert's Program, Boston Children's Hospital
Accession: SCV001146678.2
First in ClinVar: Jan 26, 2020 Last updated: Apr 13, 2025 |
Comment:
show
This variant is classified as a Variant of Uncertain Significance based on the following ACMG/AMP criteria: BS2, PP3, and PS3. Published functional in vitro and in vivio evidence (Wang et al 2007, Anderson et al 2017) supports this variant having an effect on the SCN5A protein, but population frequency (MAF of 0.0003 in non-finnish Europeans) is high compared to frequency of disease. (less)
Observation 1
Collection method: research
Allele origin: maternal
Affected status: unknown
Indication for testing: Sudden death in Childhood
Sex: male
Platform type: Next-generation exome sequencing
|
|
|
Uncertain significance
(Jul 11, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Not Provided |
GeneDx
Accession: SCV000235458.18
First in ClinVar: Jul 05, 2015 Last updated: Jul 19, 2025 |
Comment:
show
Reported in individuals with various cardiac phenotypes, including LQTS, Brugada syndrome, lone atrial fibrillation, sudden infant death syndrome, cardiomyopathy, and T-wave inversion (PMID: 17210839, 10508990, 10973849, 19716085, 22685113, 25210526, 23465283, 29764897, 31514951, 34065239); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Functional studies have been reported and show conflicting results (PMID: 17210841, 24613995); This variant is associated with the following publications: (PMID: 10973849, 19716085, 28316956, 31514951, 30193851, 22685113, 23465283, 22378279, 25637381, 25210526, 10961955, 18503232, 23272275, 24055113, 24613995, 25351510, 25410959, 25904541, 25898860, 27153395, 29247119, 28412158, 28341588, 30677491, 28988457, 31019283, 31043699, 32048431, 30291343, 30847666, 29764897, 26743238, 19841300, 24144883, 24631775, 26746457, 31395126, 34426522, 34065239, 34621001, 34461752, 33772059, 35060774, 30203441, 10508990, 17210839, 29790872, 17210841, 37937776, 36396199, 35534676, 36129056, 37965733) (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Uncertain significance
(-)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
SCN5A-related disorder
|
Daryl Scott Lab, Baylor College of Medicine
Accession: SCV006555392.1
First in ClinVar: Oct 18, 2025 Last updated: Oct 18, 2025 |
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
Zygosity: Single Heterozygote
|
|
|
Uncertain significance
(May 01, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
CeGaT Center for Human Genetics Tuebingen
Accession: SCV005050815.15
First in ClinVar: Jun 17, 2024 Last updated: Jan 11, 2026 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
|
|
|
Uncertain significance
(Mar 31, 2017)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not provided |
Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000924952.1
First in ClinVar: Jun 29, 2019 Last updated: Jun 29, 2019 |
Observation: 1
Collection method: provider interpretation
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: provider interpretation
Allele origin: germline
Affected status: unknown
|
|
|
Uncertain significance
(Apr 01, 2024)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
SCN5A-related condition
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004754871.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
show
The SCN5A c.3911C>T variant is predicted to result in the amino acid substitution p.Thr1304Met. This variant was reported in individuals with long QT syndrome and Brugada syndrome (Wattanasirichaigoon et al. 1999. PMID: 10508990; Arnestad et al. 2007. PMID: 17210839; Kapplinger et al. 2009. PMID: 19716085; Kapa et al. 2009. PMID: 19841300; Table SVI, Milman et al. 2021. PubMed ID: 34461752). Functional studies showed conflicting evidences of pathogenicity for this variant. Although one study suggested this variant significantly increased persistent sodium currents and faster recovery from inactivation (Wang et al. 2007. PMID: 17210841), another demonstrated no difference from wild type SCN5A (Beyder et al. 2014. PubMed ID: 24613995). This variant also had conflicting interpretations of pathogenicity in the literature ranging from benign to pathogenic (Table S1, Amendola et al. 2015. PMID: 25637381; Table S1, Paludan-Müller et al. 2019. PubMed ID: 31043699; Table SVI, Milman et al. 2021. PubMed ID: 34461752). This variant is reported in 0.031% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations of benign, uncertain significance, likely pathogenic, and pathogenic in ClinVar (www.ncbi.nlm.nih.gov/clinvar/variation/67835/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Sep 13, 2013)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Long QT syndrome 3
GERMLINE
(Autosomal dominant inheritance)
|
Donald Williams Parsons Laboratory, Baylor College of Medicine
Additional submitter:
Donald Williams Parsons Laboratory, Baylor College of Medicine
Study: CSER-BASIC3
Accession: SCV000599943.2 First in ClinVar: Jul 30, 2017 Last updated: Apr 13, 2025 |
Comment:
show
This variant has been previously reported as disease-causing. It was an incidental finding in our study, maternally inherited in a 8-year-old male with medulloblastoma. (less)
Observation 1
Collection method: research
Allele origin: maternal
Affected status: unknown
Number of individuals with the variant: 1
Zygosity: Single Heterozygote
Age: 0-9 years
Sex: male
Ethnicity/Population group: Causasians
Secondary finding: yes
Platform type: Next-gen sequencing
|
|
|
not provided
(-)
N
Not contributing to aggregate classification
|
no classification provided
|
Congenital long QT syndrome |
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust
Accession: SCV000090133.3
First in ClinVar: Oct 22, 2013 Last updated: Oct 09, 2016 |
Comment:
show
This variant has been reported as associated with Long QT syndrome in the following publications (PMID:10508990;PMID:10961955;PMID:17210839;PMID:19716085;PMID:19841300;PMID:17210841;PMID:22378279;PMID:22685113). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. (less)
Observation: 1
Collection method: literature only
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: literature only
Allele origin: germline
Affected status: unknown
|
|
|
Likely pathogenic
(Jun 01, 2014)
N
Not contributing to aggregate classification
|
Flagged submission
flagged submission
Reason: Claim with insufficient supporting evidence
Source: ClinGen
|
Long QT syndrome
(Autosomal dominant inheritance)
|
CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190588.1 First in ClinVar: Dec 06, 2014 Last updated: Dec 06, 2014
Comment:
Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
|
Observation: 1
Collection method: research
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: research
Allele origin: germline
Affected status: unknown
|
|
|
Likely pathogenic
(Jan 13, 2017)
N
Not contributing to aggregate classification
|
Flagged submission
flagged submission
Reason: Claim with insufficient supporting evidence
Source: ClinGen
|
Brugada syndrome |
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital
Accession: SCV000805033.1
First in ClinVar: Sep 13, 2018 Last updated: Sep 13, 2018 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Likely pathogenic
(Nov 21, 2018)
N
Not contributing to aggregate classification
|
Flagged submission
flagged submission
Reason: Claim with insufficient supporting evidence
Source: ClinGen
|
Long QT syndrome 3 |
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV000883131.1
First in ClinVar: May 30, 2018 Last updated: May 30, 2018 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Comment:
Comment:
The SCN5A c.3911C>T; p.Thr1304Met variant (rs199473603) is reported in the literature in individuals affected with long QT syndrome (Kapa 2009, Wattanasirichaigoon 1999) or Brugada syndrome (Kim 2014), which have different mechanisms of pathogenicity. This variant is also reported with conflicting interpretations by multiple laboratories in ClinVar (Variation ID: 67835), and is found in the non-Finnish European population with an allele frequency of 0.031% (40/127748 alleles) in the Genome Aggregation Database. The threonine at codon 1304 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, functional analyses of the variant protein show conflicting effects on channel function (Beyder 2014, Wang 2007). Due to conflicting information, the clinical significance of the p.Thr1304Met variant is uncertain at this time. References: Beyder A et al. Loss-of-function of the voltage-gated sodium channel NaV1.5 (channelopathies) in patients with irritable bowel syndrome. Gastroenterology. 2014 Jun;146(7):1659-1668. Kapa S et al. Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants. Circulation. 2009 Nov 3;120(18):1752-60. Kim G et al. A pediatric case of Brugada syndrome diagnosed by fever-provoked ventricular tachycardia. Korean J Pediatr. 2014 Aug;57(8):374-8. Wang DW et al. Cardiac sodium channel dysfunction in sudden infant death syndrome. Circulation. 2007 Jan 23;115(3):368-76. Wattanasirichaigoon D et al. Sodium channel abnormalities are infrequent in patients with long QT syndrome: identification of two novel SCN5A mutations. Am J Med Genet. 1999 Oct 29;86(5):470-6.
Comment:
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1304 of the SCN5A protein (p.Thr1304Met). This variant is present in population databases (rs199473603, gnomAD 0.03%). This missense change has been observed in individual(s) with SCN5A-related conditions (PMID: 10508990, 17210839, 17210841, 19716085, 19841300, 24631775, 25210526, 28341588, 30847666). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 67835). 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: 17210841). 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.
Comment:
The SCN5A c.3911C>T variant (rs199473603) is present in population databases (gnomAD 0.03%). Computational prediction analyses (Polyphen-2, SIFT) suggest that this variant has deleterious effect on protein structure and function. Functional studies have shown conflicting results in channel function (PMID: 17210841, 24613995). This variant was reported in individuals with long QT syndrome (PMID: 17210839, 19716085, 19841300); Brugada syndrome (PMID: 34461752, 25210526), sudden unexplained death (PMID: 17210839, 17210841, 24631775, 32652122). Based on conflicting evidence, the clinical role of SCN5A c.3911C>T variant cannot be determined. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
The p.T1304M variant (also known as c.3911C>T), located in coding exon 21 of the SCN5A gene, results from a C to T substitution at nucleotide position 3911. The threonine at codon 1304 is replaced by methionine, an amino acid with similar properties, and is located in the transmembrane DIII-S4 region. This alteration has been reported in association with long QT syndrome (Wattanasirichaigoon D et al. Am. J. Med. Genet., 1999 Oct;86:470-6; Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303). In one family, alteration carriers showed variable clinical and electrophysiological phenotypes with several having borderline findings (Wattanasirichaigoon D et al. Am. J. Med. Genet., 1999 Oct;86:470-6). This alteration was also detected in individuals with a transient Brugada pattern, lone atrial fibrillation, or sudden infant death syndrome (Wang DW et al. Circulation, 2007 Jan;115:368-76; Olesen MS et al. Circ Cardiovasc Genet, 2012 Aug;5:450-9; Wang D et al. Forensic Sci. Int., 2014 Apr;237:90-9; Kim G et al. Korean J Pediatr, 2014 Aug;57:374-8). In addition, this alteration was reported in hypertrophic cardiomyopathy, dilated cardiomyopathy cohorts as well as exome sequencing and cohorts not selected for the presence of cardiovascular disease; however, limited clinical information was provided (Andreasen C et al. Can J Cardio. 2013;29(9):1104-9; Dorschner MO et al. Am J Hum Genet. 2013;93(4):631-40; Lopes LR et al. Heart, 2015 Feb;101:294-301; Amendola LM et al. Genome Res., 2015 Mar;25:305-15; Van Driest SL et al. JAMA, 2016 Jan;315:47-57; Gigli M et al. J Am Coll Cardiol. 2019 09;74(11):1480-1490; Diebold I et al. Hum Mutat. 2020 05;41(5):1025-1032). While some research groups reported that this alteration would lead to gain of function effects (Wang DW et al. Circulation, 2007 Jan;115:368-76; Arnestad M et al. Circulation, 2007 Jan;115:361-7), others found no significant difference between mutant and wild type channel function (Beyder A et al. Gastroenterology, 2014 Jun;146:1659-1668; Makita N et al. J. Clin. Invest., 2008 Jun;118:2219-29); however, the experimental systems were not the same and the physiological significance of these results is unclear. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Comment:
Variant summary: SCN5A c.3911C>T (p.Thr1304Met) 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 0.00018 in 247644 control chromosomes. The observed variant frequency is approximately 8.53 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Long QT Syndrome phenotype (2.1e-05). c.3911C>T has been reported in the literature in individuals affected with Long QT Syndrome and other related conditions (e.g. Wattanasirichaigoon_1999, Arnestad_2007, Kapplinger_2009, Kapa_2009, van Lint_2019). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and demonstrates an affect on protein function (Wang_2007). The following publications have been ascertained in the context of this evaluation (PMID: 17210839, 37937776, 35534676, 19841300, 19716085, 36396199, 17210841, 10508990, 39486665, 36129056, 30847666). ClinVar contains an entry for this variant (Variation ID: 67835). Based on the evidence outlined above, the variant was classified as uncertain significance.
Comment:
PM1, PP2, PP3, BS1
Comment:
PP1, PP3_moderate
Comment:
This variant is classified as a Variant of Uncertain Significance based on the following ACMG/AMP criteria: BS2, PP3, and PS3. Published functional in vitro and in vivio evidence (Wang et al 2007, Anderson et al 2017) supports this variant having an effect on the SCN5A protein, but population frequency (MAF of 0.0003 in non-finnish Europeans) is high compared to frequency of disease.
Comment:
Reported in individuals with various cardiac phenotypes, including LQTS, Brugada syndrome, lone atrial fibrillation, sudden infant death syndrome, cardiomyopathy, and T-wave inversion (PMID: 17210839, 10508990, 10973849, 19716085, 22685113, 25210526, 23465283, 29764897, 31514951, 34065239); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Functional studies have been reported and show conflicting results (PMID: 17210841, 24613995); This variant is associated with the following publications: (PMID: 10973849, 19716085, 28316956, 31514951, 30193851, 22685113, 23465283, 22378279, 25637381, 25210526, 10961955, 18503232, 23272275, 24055113, 24613995, 25351510, 25410959, 25904541, 25898860, 27153395, 29247119, 28412158, 28341588, 30677491, 28988457, 31019283, 31043699, 32048431, 30291343, 30847666, 29764897, 26743238, 19841300, 24144883, 24631775, 26746457, 31395126, 34426522, 34065239, 34621001, 34461752, 33772059, 35060774, 30203441, 10508990, 17210839, 29790872, 17210841, 37937776, 36396199, 35534676, 36129056, 37965733)
Comment:
BS2, BP5, PS3_supporting, PP3
Comment:
SCN5A: PP3
Comment:
The SCN5A c.3911C>T variant is predicted to result in the amino acid substitution p.Thr1304Met. This variant was reported in individuals with long QT syndrome and Brugada syndrome (Wattanasirichaigoon et al. 1999. PMID: 10508990; Arnestad et al. 2007. PMID: 17210839; Kapplinger et al. 2009. PMID: 19716085; Kapa et al. 2009. PMID: 19841300; Table SVI, Milman et al. 2021. PubMed ID: 34461752). Functional studies showed conflicting evidences of pathogenicity for this variant. Although one study suggested this variant significantly increased persistent sodium currents and faster recovery from inactivation (Wang et al. 2007. PMID: 17210841), another demonstrated no difference from wild type SCN5A (Beyder et al. 2014. PubMed ID: 24613995). This variant also had conflicting interpretations of pathogenicity in the literature ranging from benign to pathogenic (Table S1, Amendola et al. 2015. PMID: 25637381; Table S1, Paludan-Müller et al. 2019. PubMed ID: 31043699; Table SVI, Milman et al. 2021. PubMed ID: 34461752). This variant is reported in 0.031% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations of benign, uncertain significance, likely pathogenic, and pathogenic in ClinVar (www.ncbi.nlm.nih.gov/clinvar/variation/67835/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Comment:
This variant has been previously reported as disease-causing. It was an incidental finding in our study, maternally inherited in a 8-year-old male with medulloblastoma.
Comment:
This variant has been reported as associated with Long QT syndrome in the following publications (PMID:10508990;PMID:10961955;PMID:17210839;PMID:19716085;PMID:19841300;PMID:17210841;PMID:22378279;PMID:22685113). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Variants that get straight to your heart - Cardiogenetic secondary findings in exome sequencing. | Wenderholm K | Gene | 2025 | PMID: 39486665 |
| Actionable Genotypes and Their Association with Life Span in Iceland. | Jensson BO | The New England journal of medicine | 2023 | PMID: 37937776 |
| Prognostic Prediction of Genotype vs Phenotype in Genetic Cardiomyopathies. | Paldino A | Journal of the American College of Cardiology | 2022 | PMID: 36396199 |
| Determining the Likelihood of Disease Pathogenicity Among Incidentally Identified Genetic Variants in Rare Dilated Cardiomyopathy-Associated Genes. | Yang Q | Journal of the American Heart Association | 2022 | PMID: 36129056 |
| A commentary on actionable secondary findings in the 73 ACMG-recommended genes in 1559 Thai exomes. | Johnston JJ | Journal of human genetics | 2022 | PMID: 35534676 |
| Genotype-Phenotype Correlation of SCN5A Genotype in Patients With Brugada Syndrome and Arrhythmic Events: Insights From the SABRUS in 392 Probands. | Milman A | Circulation. Genomic and precision medicine | 2021 | PMID: 34461752 |
| The genetic structure of the Turkish population reveals high levels of variation and admixture. | Kars ME | Proceedings of the National Academy of Sciences of the United States of America | 2021 | PMID: 34426522 |
| A de novo BRPF1 variant in a case of Sudden Unexplained Death in Childhood. | Keywan C | European journal of medical genetics | 2020 | PMID: 32652122 |
| Critical assessment of secondary findings in genes linked to primary arrhythmia syndromes. | Diebold I | Human mutation | 2020 | PMID: 32048431 |
| Reappraisal of variants previously linked with sudden infant death syndrome: results from three population-based cohorts. | Paludan-Müller C | European journal of human genetics : EJHG | 2019 | PMID: 31043699 |
| Secondary actionable findings identified by exome sequencing: expected impact on the organisation of care from the study of 700 consecutive tests. | Thauvin-Robinet C | European journal of human genetics : EJHG | 2019 | PMID: 31019283 |
| Large next-generation sequencing gene panels in genetic heart disease: yield of pathogenic variants and variants of unknown significance. | van Lint FHM | Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation | 2019 | PMID: 30847666 |
| Genomic sequencing identifies secondary findings in a cohort of parent study participants. | Thompson ML | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 29790872 |
| Diagnostic Yield of Genetic Testing in Young Athletes With T-Wave Inversion. | Sheikh N | Circulation | 2018 | PMID: 29764897 |
| A New Approach to Rare Diseases of Children: The Undiagnosed Diseases Network. | Reuter CM | The Journal of pediatrics | 2018 | PMID: 29331327 |
| Re-evaluating pathogenicity of variants associated with the long QT syndrome. | Kaltman JR | Journal of cardiovascular electrophysiology | 2018 | PMID: 28988457 |
| 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 |
| Lidocaine attenuation testing: An in vivo investigation of putative LQT3-associated variants in the SCN5A-encoded sodium channel. | Anderson HN | Heart rhythm | 2017 | PMID: 28412158 |
| Targeted Next-Generation Sequencing of 51 Genes Involved in Primary Electrical Disease. | Proost D | The Journal of molecular diagnostics : JMD | 2017 | PMID: 28341588 |
| Association of Arrhythmia-Related Genetic Variants With Phenotypes Documented in Electronic Medical Records. | Van Driest SL | JAMA | 2016 | PMID: 26746457 |
| Patient Outcomes From a Specialized Inherited Arrhythmia Clinic. | Adler A | Circulation. Arrhythmia and electrophysiology | 2016 | PMID: 26743238 |
| 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 |
| Actionable exomic incidental findings in 6503 participants: challenges of variant classification. | Amendola LM | Genome research | 2015 | PMID: 25637381 |
| Examining rare and low-frequency genetic variants previously associated with lone or familial forms of atrial fibrillation in an electronic medical record system: a cautionary note. | Weeke P | Circulation. Cardiovascular genetics | 2015 | PMID: 25410959 |
| Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy. | Lopes LR | Heart (British Cardiac Society) | 2015 | PMID: 25351510 |
| A pediatric case of Brugada syndrome diagnosed by fever-provoked ventricular tachycardia. | Kim G | Korean journal of pediatrics | 2014 | PMID: 25210526 |
| Cardiac channelopathy testing in 274 ethnically diverse sudden unexplained deaths. | Wang D | Forensic science international | 2014 | PMID: 24631775 |
| Loss-of-function of the voltage-gated sodium channel NaV1.5 (channelopathies) in patients with irritable bowel syndrome. | Beyder A | Gastroenterology | 2014 | PMID: 24613995 |
| Very early-onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation. | Olesen MS | Heart rhythm | 2014 | PMID: 24144883 |
| Actionable, pathogenic incidental findings in 1,000 participants' exomes. | Dorschner MO | American journal of human genetics | 2013 | PMID: 24055113 |
| Mutations in genes encoding cardiac ion channels previously associated with sudden infant death syndrome (SIDS) are present with high frequency in new exome data. | Andreasen C | The Canadian journal of cardiology | 2013 | PMID: 23465283 |
| High prevalence of long QT syndrome-associated SCN5A variants in patients with early-onset lone atrial fibrillation. | Olesen MS | Circulation. Cardiovascular genetics | 2012 | PMID: 22685113 |
| High prevalence of genetic variants previously associated with LQT syndrome in new exome data. | Refsgaard L | European journal of human genetics : EJHG | 2012 | PMID: 22378279 |
| Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants. | Kapa S | Circulation | 2009 | PMID: 19841300 |
| 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 |
| The E1784K mutation in SCN5A is associated with mixed clinical phenotype of type 3 long QT syndrome. | Makita N | The Journal of clinical investigation | 2008 | PMID: 18451998 |
| Letter by O'Rourke regarding articles, "Prevalence of long-QT syndrome gene variants in sudden infant death syndrome," "Cardiac sodium channel dysfunction in sudden infant death syndrome," and "Contribution of long-QT syndrome genes to sudden infant death syndrome: is it time to consider newborn electrocardiographic screening?". | O'Rourke MF | Circulation | 2007 | PMID: 17646591 |
| Cardiac sodium channel dysfunction in sudden infant death syndrome. | Wang DW | Circulation | 2007 | PMID: 17210841 |
| Prevalence of long-QT syndrome gene variants in sudden infant death syndrome. | Arnestad M | Circulation | 2007 | PMID: 17210839 |
| Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. | Splawski I | Circulation | 2000 | PMID: 10973849 |
| The elusive link between LQT3 and Brugada syndrome: the role of flecainide challenge. | Priori SG | Circulation | 2000 | PMID: 10961955 |
| Sodium channel abnormalities are infrequent in patients with long QT syndrome: identification of two novel SCN5A mutations. | Wattanasirichaigoon D | American journal of medical genetics | 1999 | PMID: 10508990 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SCN5A | - | - | - | - |
| click to load more citations click to collapse | ||||
Submissions - Functional Data
functionally normal
--
functionally normal
assessed by
patch clamp
3
0.5
severe loss-of-function
-4
mild-moderate loss-of-function
-2
no loss-of-function
this variant -1.93
This variant was studied in an automated patch clamp assay (PMID: 38953211). The assay was validated with benign and pathogenic control variants using ClinGen’s OddsPath framework. 'Normal' function is defined as a z-score within ±2, with more negative z-scores indicating greater loss-of-function. This variant had a mean functional z-score of -1.93, falls within the range of normal function. Based on this result, the recommended ACMG evidence criteria for this variant is BS3_supporting
Citation:
PubMed: 38953211
,
PubMed: 41251004
Accession: SCV007294456.1
Submitted: 2025-12-09
Assay description:
Functional assay results from automated patch clamp platform evaluating the ion channel electrophysiology of SCN5A variants. Functional Z-scores are calculated from the magnitude of change away from a set of benign variant controls. Variant outcomes are categorised based on assay thresholds and OddsPath calculations to determine the strength of functional evidence applicable for ACMG/AMP functional evidence criteria.
- Disease context: Brugada syndrome 1
- Transcript, protein change: NM_000335.5:c.3908C>T, T1303M
- Molecular phenotype measured: ion channel function
- Cell line: HEK293
- Collection method: in vitro
- Species: human
Text-mined citations for rs199473603 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Jan 11, 2026
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.