ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.3908C>T (p.Thr1303Met)
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.3908C>T (p.Thr1303Met)
Variation ID: 67835 Accession: VCV000067835.51
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 38562467 (GRCh38) [ NCBI UCSC ] 3: 38603958 (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 Dec 6, 2014 Oct 8, 2024 May 15, 2024 - HGVS
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Nucleotide 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
- Canonical SPDI
- NC_000003.12:38562466: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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0.00020 (A)
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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
Trans-Omics for Precision Medicine (TOPMed) 0.00026
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00040
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
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. |
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SCN5A | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3779 | 4219 |
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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- | RCV000058613.11 | |
no classifications from unflagged records (1) |
no classifications from unflagged records
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Dec 7, 2023 | RCV000148846.12 | |
Uncertain significance (3) |
criteria provided, single submitter
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Jan 4, 2024 | RCV000496069.15 | |
no classifications from unflagged records (1) |
no classifications from unflagged records
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Dec 7, 2023 | RCV000470787.21 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 4, 2024 | RCV000618218.13 | |
Uncertain significance (6) |
criteria provided, multiple submitters, no conflicts
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May 1, 2024 | RCV000725469.27 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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May 14, 2020 | RCV000987206.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 17, 2020 | RCV000993797.9 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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May 15, 2024 | RCV000824759.15 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 4, 2023 | RCV001842354.11 | |
SCN5A-related disorder
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Uncertain significance (1) |
no assertion criteria provided
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Apr 1, 2024 | RCV004537261.3 |
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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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Uncertain significance
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
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Brugada syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001136455.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Uncertain significance
(Apr 20, 2018)
|
criteria provided, single submitter
Method: clinical testing
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Brugada syndrome 1
Affected status: yes
Allele origin:
maternal
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Baylor Genetics
Accession: SCV001527656.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
|
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Uncertain significance
(Jan 04, 2024)
|
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: SCV000736754.5
First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024 |
Comment:
The c.3911C>T (p.T1304M) alteration is located in exon 22 (coding exon 21) of the SCN5A gene. This alteration results from a C to T substitution … (more)
The c.3911C>T (p.T1304M) alteration is located in exon 22 (coding exon 21) of the SCN5A gene. This alteration results from a C to T substitution at nucleotide position 3911, causing the threonine (T) at amino acid position 1304 to be replaced by a methionine (M). Based on data from gnomAD, the T allele has an overall frequency of 0.017% (46/279030) total alleles studied. The highest observed frequency was 0.031% (40/127748) of European (non-Finnish) alleles. This alteration has been reported in association with long QT syndrome (Wattanasirichaigoon, 1999; Kapplinger, 2009). In one family, alteration carriers showed variable clinical and electrophysiological phenotypes with several having borderline findings (Wattanasirichaigoon, 1999). This alteration was also detected in individuals with a transient Brugada pattern, lone atrial fibrillation, or sudden infant death syndrome (Wang, 2007; Olesen, 2012; Wang, 2014; Kim, 2014). 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, 2013; Dorschner, 2013; Lopes, 2015; Amendola, 2015; Van Driest, 2016; Gigli, 2019; Diebold, 2020). This amino acid position is highly conserved in available vertebrate species. While some research groups reported that this alteration would lead to gain of function effects (Wang, 2007; Arnestad, 2007), others found no significant difference between mutant and wild type channel function (Makita, 2008; Beyder, 2014); however, the experimental systems were not the same and the physiological significance of these results is unclear. This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Nov 16, 2015)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000337160.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
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Uncertain significance
(Apr 26, 2018)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000710929.2
First in ClinVar: Apr 09, 2018 Last updated: Aug 26, 2019 |
Comment:
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 … (more)
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)
Number of individuals with the variant: 8
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Uncertain significance
(Jan 17, 2020)
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criteria provided, single submitter
Method: research
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Conduction disorder of the heart
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
maternal
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Robert's Program, Boston Children's Hospital
Accession: SCV001146678.1
First in ClinVar: Jan 26, 2020 Last updated: Jan 26, 2020 |
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 … (more)
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)
Indication for testing: Sudden death in Childhood
Sex: male
|
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Uncertain significance
(May 14, 2020)
|
criteria provided, single submitter
Method: clinical testing
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Brugada syndrome 1
Affected status: unknown
Allele origin:
germline
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Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV001425372.1
First in ClinVar: Aug 01, 2020 Last updated: Aug 01, 2020 |
|
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Uncertain significance
(Feb 18, 2020)
|
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: SCV001160606.2
First in ClinVar: Feb 10, 2020 Last updated: Jan 26, 2021 |
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 … (more)
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)
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Uncertain significance
(Jan 04, 2024)
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criteria provided, single submitter
Method: research
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Long QT syndrome 3
Affected status: unknown
Allele origin:
unknown,
maternal
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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 1:
Number of individuals with the variant: 1
Observation 2:
Number of individuals with the variant: 1
|
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Uncertain significance
(Dec 04, 2023)
|
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: SCV000913703.5
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces threonine with methionine at codon 1304 of the SCN5A protein. Computational prediction tools indicate that this variant has a deleterious impact … (more)
This missense variant replaces threonine with methionine at codon 1304 of the SCN5A protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. Functional studies have shown inconsistent results regarding the impact of this variant on the SCN5A ion channel function (PMID: 17210841, 18451998). This variant has been reported in individuals affected with long QT syndrome (PMID: 19841300), early-onset lone atrial fibrillation (PMID: 22685113, 24144883), sudden unexplained death (PMID: 17210839, 17210841, 24631775, 32652122), and dilated cardiomyopathy (PMID: 36129056). This variant has been reported to segregate with long QT syndrome in multiple members of a family (PMID: 10508990). This variant has been reported in a small family with Brugada syndrome (PMID: 25210526). This variant has also been identified in 46/279030 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Due to the conflicting functional study results and appreciable allele frequency in the general population, the role of this variant in disease cannot be determined conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Jan 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000545009.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
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). … (more)
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)
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Uncertain significance
(May 15, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005185790.1
First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024 |
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 … (more)
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 9 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Long QT Syndrome phenotype (2.1e-05), strongly suggesting that the variant is benign. 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, 19841300, 19716085, 17210841, 10508990, 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)
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Uncertain significance
(Feb 22, 2024)
|
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: SCV000235458.16
First in ClinVar: Jul 05, 2015 Last updated: Sep 16, 2024 |
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, … (more)
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) (less)
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Uncertain significance
(May 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV005050815.4
First in ClinVar: Jun 17, 2024 Last updated: Oct 08, 2024 |
Comment:
SCN5A: PP3
Number of individuals with the variant: 1
|
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Uncertain significance
(Mar 31, 2017)
|
no assertion criteria provided
Method: provider interpretation
|
not provided
Affected status: unknown
Allele origin:
germline
|
Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000924952.1
First in ClinVar: Jun 29, 2019 Last updated: Jun 29, 2019 |
|
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Uncertain significance
(Apr 01, 2024)
|
no assertion criteria provided
Method: clinical testing
|
SCN5A-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004754871.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
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 … (more)
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)
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not provided
(-)
|
no classification provided
Method: literature only
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Congenital long QT syndrome
Affected status: unknown
Allele origin:
germline
|
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:
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 … (more)
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)
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Pathogenic
(Sep 13, 2013)
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Flagged submission
flagged submission
Method: research
Reason: Claim with insufficient supporting evidence
Source: ClinGen
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Long QT syndrome 3
GERMLINE
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
maternal
|
Donald Williams Parsons Laboratory, Baylor College of Medicine
Additional submitter:
Donald Williams Parsons Laboratory, Baylor College of Medicine
Study: CSER-BASIC3
Accession: SCV000599943.1 First in ClinVar: Jul 30, 2017 Last updated: Jul 30, 2017 |
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.
Number of individuals with the variant: 1
Age: 0-9 years
Sex: male
Ethnicity/Population group: Causasians
Secondary finding: yes
|
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Likely pathogenic
(Jan 13, 2017)
|
Flagged submission
flagged submission
Method: clinical testing
Reason: Claim with insufficient supporting evidence
Source: ClinGen
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Brugada syndrome
Affected status: yes
Allele origin:
germline
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Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital
Accession: SCV000805033.1
First in ClinVar: Sep 13, 2018 Last updated: Sep 13, 2018 |
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Likely pathogenic
(Jun 01, 2014)
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Flagged submission
flagged submission
Method: research
Reason: Claim with insufficient supporting evidence
Source: ClinGen
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Long QT syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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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
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Likely pathogenic
(Nov 21, 2018)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Claim with insufficient supporting evidence
Source: ClinGen
|
Long QT syndrome 3
Affected status: unknown
Allele origin:
unknown
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV000883131.1
First in ClinVar: May 30, 2018 Last updated: May 30, 2018 |
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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 |
---|---|---|---|---|
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 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 |
Genetic Risk of Arrhythmic Phenotypes in Patients With Dilated Cardiomyopathy. | Gigli M | Journal of the American College of Cardiology | 2019 | PMID: 31514951 |
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 |
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 |
An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing. | Kapplinger JD | Heart rhythm | 2010 | PMID: 20129283 |
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 | - | - | - | - |
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Text-mined citations for rs199473603 ...
HelpRecord last updated Oct 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.