ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.4015G>A (p.Val1339Ile)
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.
Pathogenic(1); Uncertain significance(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000335.5(SCN5A):c.4015G>A (p.Val1339Ile)
Variation ID: 67849 Accession: VCV000067849.55
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 38560374 (GRCh38) [ NCBI UCSC ] 3: 38601865 (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 Jan 31, 2016 May 1, 2024 Jan 19, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000335.5:c.4015G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000326.2:p.Val1339Ile missense NM_001099404.2:c.4018G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001092874.1:p.Val1340Ile missense NM_001099405.2:c.4018G>A NP_001092875.1:p.Val1340Ile missense NM_001160160.2:c.4015G>A NP_001153632.1:p.Val1339Ile missense NM_001160161.2:c.3856G>A NP_001153633.1:p.Val1286Ile missense NM_001354701.2:c.4015G>A NP_001341630.1:p.Val1339Ile missense NM_198056.3:c.4018G>A NP_932173.1:p.Val1340Ile missense NC_000003.12:g.38560374C>T NC_000003.11:g.38601865C>T NG_008934.1:g.94299G>A LRG_289:g.94299G>A LRG_289t1:c.4018G>A LRG_289p1:p.Val1340Ile - Protein change
- V1339I, V1340I, V1286I
- Other names
- p.V1340I:GTC>ATC
- Canonical SPDI
- NC_000003.12:38560373:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00004
Exome Aggregation Consortium (ExAC) 0.00005
The Genome Aggregation Database (gnomAD), exomes 0.00005
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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 |
3770 | 4208 |
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) |
criteria provided, single submitter
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- | RCV000058628.19 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jan 19, 2024 | RCV000183058.13 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Apr 3, 2023 | RCV001842357.13 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 30, 2022 | RCV004019050.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Oct 11, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cardiac arrhythmia
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV001347654.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces valine with isoleucine at codon 1340 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces valine with isoleucine at codon 1340 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant markedly reduces sodium currents in vitro (PMID: 19648062). This variant has been reported in four individuals affected with and in one individual suspected of having Brugada syndrome (PMID: 19648062, 20129283, 20609320, 30662450, 32268277), in four unaffected relatives from one of the affected families (PMID: 20609320), and in two individuals with borderline ECG alternations (PMID: 34428338). This variant has also been identified in 13/282822 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Pathogenic
(Jan 19, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000259420.9
First in ClinVar: Jan 31, 2016 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1340 of the SCN5A protein (p.Val1340Ile). … (more)
This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1340 of the SCN5A protein (p.Val1340Ile). This variant is present in population databases (rs199473605, gnomAD 0.04%). This missense change has been observed in individuals with Brugada syndrome (PMID: 19648062, 20129283, 20609320, 30662450; Invitae). ClinVar contains an entry for this variant (Variation ID: 67849). 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: 19648062). For these reasons, this variant has been classified as Pathogenic. (less)
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Uncertain significance
(Mar 30, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV004943837.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
The c.4018G>A (p.V1340I) alteration is located in exon 23 (coding exon 22) of the SCN5A gene. This alteration results from a G to A substitution … (more)
The c.4018G>A (p.V1340I) alteration is located in exon 23 (coding exon 22) of the SCN5A gene. This alteration results from a G to A substitution at nucleotide position 4018, causing the valine (V) at amino acid position 1340 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Dec 18, 2020)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000235467.9
First in ClinVar: Jul 05, 2015 Last updated: Jan 07, 2017 |
Comment:
Reported in association with Brugada syndrome; however, this variant was also reported in multiple unaffected family members (Samani et al., 2009; Kapplinger et al., 2010; … (more)
Reported in association with Brugada syndrome; however, this variant was also reported in multiple unaffected family members (Samani et al., 2009; Kapplinger et al., 2010; Garcia-Castro et al., 2010); In silico analysis supports that this missense variant does not alter protein structure/function; Functional studies suggest the presence of this variant may alter protein interactions under various experimental conditions; nevertheless, it is unclear how these studies may translate to a pathogenic role in vivo (Samani et al., 2009); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID#67849; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 25925977, 32268277, 19648062, 24136861, 20129283, 26633542, 25608792, 25904541, 25163546, 20609320, 22643347, 29557500, 30662450, 22581653, 33131149) (less)
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Uncertain Significance
(Apr 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiac arrhythmia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004816432.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
This missense variant replaces valine with isoleucine at codon 1340 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces valine with isoleucine at codon 1340 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant markedly reduces sodium currents in vitro (PMID: 19648062). This variant has been reported in four individuals affected with and in one individual suspected of having Brugada syndrome (PMID: 19648062, 20129283, 20609320, 30662450, 32268277), in four unaffected relatives from one of the affected families (PMID: 20609320), and in two individuals with borderline ECG alternations (PMID: 34428338). This variant has also been identified in 13/282822 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 2
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not provided
(-)
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no classification provided
Method: literature only
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Brugada syndrome
Affected status: unknown
Allele origin:
germline
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Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust
Accession: SCV000090148.3
First in ClinVar: Oct 22, 2013 Last updated: Jan 31, 2016 |
Comment:
This variant has been reported as associated with Brugada syndrome in the following publications (PMID:19648062;PMID:20129283). This is a literature report, and does not necessarily reflect … (more)
This variant has been reported as associated with Brugada syndrome in the following publications (PMID:19648062;PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Actionable genomic variants in 6045 participants from the Qatar Genome Program. | Elfatih A | Human mutation | 2021 | PMID: 34428338 |
Reanalysis and reclassification of rare genetic variants associated with inherited arrhythmogenic syndromes. | Campuzano O | EBioMedicine | 2020 | PMID: 32268277 |
Impact of Ancestral Differences and Reassessment of the Classification of Previously Reported Pathogenic Variants in Patients With Brugada Syndrome in the Genomic Era: A SADS-TW BrS Registry. | Chen CJ | Frontiers in genetics | 2019 | PMID: 30662450 |
The spectrum of SCN5A gene mutations in Spanish Brugada syndrome patients. | García-Castro M | Revista espanola de cardiologia | 2010 | PMID: 20609320 |
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 |
A novel SCN5A mutation V1340I in Brugada syndrome augmenting arrhythmias during febrile illness. | Samani K | Heart rhythm | 2009 | PMID: 19648062 |
Text-mined citations for rs199473605 ...
HelpRecord last updated Sep 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.