ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.2182G>A (p.Val728Ile)
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.2182G>A (p.Val728Ile)
Variation ID: 633412 Accession: VCV000633412.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 38597809 (GRCh38) [ NCBI UCSC ] 3: 38639300 (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 Jun 3, 2019 Apr 20, 2024 Aug 17, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000335.5:c.2182G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000326.2:p.Val728Ile missense NM_001099404.2:c.2182G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001092874.1:p.Val728Ile missense NM_001099405.2:c.2182G>A NP_001092875.1:p.Val728Ile missense NM_001160160.2:c.2182G>A NP_001153632.1:p.Val728Ile missense NM_001160161.2:c.2182G>A NP_001153633.1:p.Val728Ile missense NM_001354701.2:c.2182G>A NP_001341630.1:p.Val728Ile missense NM_198056.3:c.2182G>A NP_932173.1:p.Val728Ile missense NC_000003.12:g.38597809C>T NC_000003.11:g.38639300C>T NG_008934.1:g.56864G>A LRG_289:g.56864G>A LRG_289t1:c.2182G>A LRG_289p1:p.Val728Ile LRG_289t2:c.2182G>A LRG_289p2:p.Val728Ile - Protein change
- V728I
- Other names
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- Canonical SPDI
- NC_000003.12:38597808: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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD) 0.00002
- 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 | ||
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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 |
3724 | 4156 |
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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Uncertain significance (1) |
criteria provided, single submitter
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Dec 18, 2017 | RCV000781842.9 | |
Uncertain significance (1) |
no assertion criteria provided
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Apr 7, 2020 | RCV001254736.9 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Aug 17, 2023 | RCV001759475.11 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Apr 3, 2023 | RCV001841974.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 16, 2020 | RCV002424779.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 16, 2021 | RCV002487613.8 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Dec 18, 2017)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000920199.1
First in ClinVar: Jun 03, 2019 Last updated: Jun 03, 2019 |
Comment:
Variant summary: The SCN5A c.2182G>A (p.Val728Ile) variant involves the alteration of a conserved nucleotide located in the Ion transport domain (IPR005821) (InterPro). 2/4 in silico … (more)
Variant summary: The SCN5A c.2182G>A (p.Val728Ile) variant involves the alteration of a conserved nucleotide located in the Ion transport domain (IPR005821) (InterPro). 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 2/246420 control chromosomes (gnomAD and Garca-Molina_2013) at a frequency of 0.0000081, which does not exceed the estimated maximal expected allele frequency of a pathogenic SCN5A variant (0.0001). This variant was reported in one patient with Brugada syndrome without strong evidence for causality (Garca-Molina_2013). Taken together, this variant is classified as VUS until additional evidence becomes available. (less)
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Uncertain significance
(Mar 16, 2020)
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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: SCV002729379.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.V728I variant (also known as c.2182G>A), located in coding exon 13 of the SCN5A gene, results from a G to A substitution at nucleotide … (more)
The p.V728I variant (also known as c.2182G>A), located in coding exon 13 of the SCN5A gene, results from a G to A substitution at nucleotide position 2182. The valine at codon 728 is replaced by isoleucine, an amino acid with highly similar properties. This variant has been reported in an asymptomatic patient in a Brugada syndrome cohort (García-Molina E et al. Clin. Genet., 2013 Jun;83:530-8). This amino acid position is well conserved in available vertebrate species; however, isoleucine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Sep 16, 2021)
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criteria provided, single submitter
Method: clinical testing
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Progressive familial heart block, type 1A
SUDDEN INFANT DEATH SYNDROME Brugada syndrome 1 Dilated cardiomyopathy 1E Ventricular fibrillation, paroxysmal familial, type 1 Long QT syndrome 3 Sick sinus syndrome 1 Atrial fibrillation, familial, 10
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002789666.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Oct 14, 2021)
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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: SCV001987407.2
First in ClinVar: Nov 06, 2021 Last updated: Mar 04, 2023 |
Comment:
Reported in a cohort of individuals with Brugada syndrome, however, patient-specific data were not provided (Ciconte et al., 2021); Not observed at significant frequency in … (more)
Reported in a cohort of individuals with Brugada syndrome, however, patient-specific data were not provided (Ciconte et al., 2021); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 633412; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 30662450, 26582918, 22984773, 33221895) (less)
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Uncertain significance
(Dec 02, 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: SCV001349577.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces valine with isoleucine at codon 728 of the SCN5A protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact … (more)
This missense variant replaces valine with isoleucine at codon 728 of the SCN5A protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with Brugada syndrome (PMID: 22984773) and in an individual affected with early repolarization syndrome (PMID: 34649698). This variant has also been identified in 3/280656 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Aug 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001556999.3
First in ClinVar: Apr 13, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 728 of the SCN5A protein (p.Val728Ile). … (more)
This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 728 of the SCN5A protein (p.Val728Ile). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with Brugada syndrome and/or SCN5A-related conditions (PMID: 14985827, 22984773, 33221895). ClinVar contains an entry for this variant (Variation ID: 633412). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain Significance
(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: SCV004821607.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
This missense variant replaces valine with isoleucine at codon 728 of the SCN5A protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact … (more)
This missense variant replaces valine with isoleucine at codon 728 of the SCN5A protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with Brugada syndrome (PMID: 22984773) and in an individual affected with early repolarization syndrome (PMID: 34649698). This variant has also been identified in 3/280656 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: 3
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Uncertain significance
(Apr 07, 2020)
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no assertion criteria provided
Method: research
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Sudden cardiac arrest
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Agnes Ginges Centre for Molecular Cardiology, Centenary Institute
Accession: SCV001430818.1
First in ClinVar: Aug 23, 2020 Last updated: Aug 23, 2020 |
Comment:
This variant has been identified as part of our research program. Refer to the 'condition' field for the phenotype of the proband identified with this … (more)
This variant has been identified as part of our research program. Refer to the 'condition' field for the phenotype of the proband identified with this variant. For further information please feel free to contact us. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Distinct Features of Probands With Early Repolarization and Brugada Syndromes Carrying SCN5A Pathogenic Variants. | Zhang ZH | Journal of the American College of Cardiology | 2021 | PMID: 34649698 |
Brugada syndrome genetics is associated with phenotype severity. | Ciconte G | European heart journal | 2021 | PMID: 33221895 |
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 |
A study of the SCN5A gene in a cohort of 76 patients with Brugada syndrome. | García-Molina E | Clinical genetics | 2013 | PMID: 22984773 |
[Single nucleotide polymorphism in SCN5A and the distribution in Chinese Han ethnic group]. | Xie XD | Sheng li xue bao : [Acta physiologica Sinica] | 2004 | PMID: 14985827 |
Text-mined citations for rs958480279 ...
HelpRecord last updated Apr 20, 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.