ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.1984G>T (p.Ala662Ser)
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.1984G>T (p.Ala662Ser)
Variation ID: 523706 Accession: VCV000523706.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 38598957 (GRCh38) [ NCBI UCSC ] 3: 38640448 (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 May 21, 2018 May 1, 2024 Jan 3, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000335.5:c.1984G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000326.2:p.Ala662Ser missense NM_001099404.2:c.1984G>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001092874.1:p.Ala662Ser missense NM_001099405.2:c.1984G>T NP_001092875.1:p.Ala662Ser missense NM_001160160.2:c.1984G>T NP_001153632.1:p.Ala662Ser missense NM_001160161.2:c.1984G>T NP_001153633.1:p.Ala662Ser missense NM_001354701.2:c.1984G>T NP_001341630.1:p.Ala662Ser missense NM_198056.3:c.1984G>T NP_932173.1:p.Ala662Ser missense NC_000003.12:g.38598957C>A NC_000003.11:g.38640448C>A NG_008934.1:g.55716G>T LRG_289:g.55716G>T LRG_289t1:c.1984G>T LRG_289p1:p.Ala662Ser - Protein change
- A662S
- Other names
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- Canonical SPDI
- NC_000003.12:38598956:C:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00012
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00011
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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SCN5A | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
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Conditions - Germline
Condition
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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 20, 2016 | RCV000627152.11 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Dec 11, 2023 | RCV001584456.15 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jan 3, 2024 | RCV001841811.13 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 18, 2022 | RCV002420656.10 |
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 20, 2016)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000747983.1
First in ClinVar: May 21, 2018 Last updated: May 21, 2018 |
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Uncertain significance
(Dec 11, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000938096.5
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 662 of the SCN5A protein (p.Ala662Ser). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 662 of the SCN5A protein (p.Ala662Ser). This variant is present in population databases (rs371313714, gnomAD 0.03%). This missense change has been observed in individual(s) with sudden unexplained death (PMID: 24631775). ClinVar contains an entry for this variant (Variation ID: 523706). 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
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV001356476.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces alanine with serine at codon 662 of the SCN5A protein. Computational prediction suggests that this variant may have a deleterious impact … (more)
This missense variant replaces alanine with serine at codon 662 of the SCN5A protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with sudden unexplained death (PMID: 24631775); it has also been reported in multiple healthy control individuals (PMID: 25904541, 34930020). This variant has been identified in 6/280220 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 13, 2019)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001819893.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
Reported in an infant with sudden unexplained death (Wang et al., 2014); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 523706; … (more)
Reported in an infant with sudden unexplained death (Wang et al., 2014); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 523706; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28316956, 24631775) (less)
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Uncertain significance
(Jun 28, 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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AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002501582.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
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Uncertain Significance
(Jan 03, 2024)
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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: SCV004833147.1
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 alanine with serine at codon 662 of the SCN5A protein. Computational prediction suggests that this variant may have a deleterious impact … (more)
This missense variant replaces alanine with serine at codon 662 of the SCN5A protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with sudden unexplained death (PMID: 24631775); it has also been reported in multiple healthy control individuals (PMID: 25904541, 34930020). This variant has been identified in 6/280220 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
(Nov 18, 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: SCV002717890.3
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.A662S variant (also known as c.1984G>T), located in coding exon 12 of the SCN5A gene, results from a G to T substitution at nucleotide … (more)
The p.A662S variant (also known as c.1984G>T), located in coding exon 12 of the SCN5A gene, results from a G to T substitution at nucleotide position 1984. The alanine at codon 662 is replaced by serine, an amino acid with similar properties. This variant has been detected in a sudden unexplained death case and co-occurred with an MYBPC3 variant in a case with noncompaction cardiomyopathy (Wang D et al. Forensic Sci. Int., 2014 Apr;237:90-9; van Lint FHM et al. Neth Heart J. 2019 Jun;27(6):304-309). This variant has also been detected in individuals from control cohorts and cohorts not selected for the presence of cardiovascular disease (Kapplinger JD et al. Circ Cardiovasc Genet, 2015 Aug;8:582-95; Glazer AM et al. Circulation. 2022 03;145(12):877-891). Functional studies suggest this variant may not significantly impact channel function; however, additional evidence is needed to confirm this finding (Glazer AM et al. Circulation. 2022 03;145(12):877-891). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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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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Arrhythmia Variant Associations and Reclassifications in the eMERGE-III Sequencing Study. | Glazer AM | Circulation | 2022 | PMID: 34930020 |
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 |
Enhanced Classification of Brugada Syndrome-Associated and Long-QT Syndrome-Associated Genetic Variants in the SCN5A-Encoded Na(v)1.5 Cardiac Sodium Channel. | Kapplinger JD | Circulation. Cardiovascular genetics | 2015 | PMID: 25904541 |
Cardiac channelopathy testing in 274 ethnically diverse sudden unexplained deaths. | Wang D | Forensic science international | 2014 | PMID: 24631775 |
Text-mined citations for rs371313714 ...
HelpRecord last updated Oct 13, 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.