ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.1763A>G (p.His588Arg)
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.1763A>G (p.His588Arg)
Variation ID: 845494 Accession: VCV000845494.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 38603839 (GRCh38) [ NCBI UCSC ] 3: 38645330 (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 Apr 15, 2020 Sep 16, 2024 Jun 13, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000335.5:c.1763A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000326.2:p.His588Arg missense NM_001099404.2:c.1763A>G MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001092874.1:p.His588Arg missense NM_001099405.2:c.1763A>G NP_001092875.1:p.His588Arg missense NM_001160160.2:c.1763A>G NP_001153632.1:p.His588Arg missense NM_001160161.2:c.1763A>G NP_001153633.1:p.His588Arg missense NM_001354701.2:c.1763A>G NP_001341630.1:p.His588Arg missense NM_198056.3:c.1763A>G NP_932173.1:p.His588Arg missense NC_000003.12:g.38603839T>C NC_000003.11:g.38645330T>C NG_008934.1:g.50834A>G LRG_289:g.50834A>G LRG_289t1:c.1763A>G LRG_289p1:p.His588Arg - Protein change
- H588R
- Other names
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- Canonical SPDI
- NC_000003.12:38603838:T:C
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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 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
- 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
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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 |
3779 | 4219 |
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
Help
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 (2) |
criteria provided, multiple submitters, no conflicts
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Jan 11, 2024 | RCV001842595.13 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 20, 2022 | RCV003541116.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 13, 2024 | RCV004702603.1 |
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
(Jan 11, 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: SCV004830411.1
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 histidine with arginine at codon 588 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces histidine with arginine at codon 588 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that the H558R channel has mutation-specific effects on other Sick Sinus Syndrome-related mutant channels (PMID: 20384651). This variant has been reported in an individual affected with torsades de pointes and complete atrioventricular block, and in another individual affected with arrhythmogenic right ventricular dysplasia (PMID: 20386770, 24317018). This variant has been identified in 1/248256 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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Uncertain significance
(Jun 13, 2024)
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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: SCV005204306.1
First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024 |
Comment:
Variant summary: SCN5A c.1763A>G (p.His588Arg) results in a non-conservative amino acid change located in the Voltage-gated Na+ ion channel, cytoplasmic domain (IPR024583) of the encoded … (more)
Variant summary: SCN5A c.1763A>G (p.His588Arg) results in a non-conservative amino acid change located in the Voltage-gated Na+ ion channel, cytoplasmic domain (IPR024583) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 248256 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1763A>G has been reported in the literature in an individual with arrhythmogenic right ventricular dysplasia (Yu_2014) without evidence for causality. These report(s) do not provide unequivocal conclusions about association of the variant with Long QT Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function and demonstrates mutation specific effects of this variant on SCN5A related Sick Sinus Syndrome (Gui_2010). The following publications have been ascertained in the context of this evaluation (PMID: 20384651, 24317018). ClinVar contains an entry for this variant (Variation ID: 845494). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Jan 20, 2022)
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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: SCV001212579.4
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 845494). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 588 of the SCN5A protein (p.His588Arg). (less)
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Uncertain significance
(Aug 24, 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: SCV001352940.4
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces histidine with arginine at codon 588 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces histidine with arginine at codon 588 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that the H558R channel has mutation-specific effects on other Sick Sinus Syndrome-related mutant channels (PMID: 20384651). This variant has been reported in an individual affected with torsades de pointes and complete atrioventricular block, and in another individual affected with arrhythmogenic right ventricular dysplasia (PMID: 20386770, 24317018). This variant has been identified in 1/248256 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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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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SCN5A mutation in Chinese patients with arrhythmogenic right ventricular dysplasia. | Yu J | Herz | 2014 | PMID: 24317018 |
Torsades de pointes during complete atrioventricular block: Genetic factors and electrocardiogram correlates. | Subbiah RN | The Canadian journal of cardiology | 2010 | PMID: 20386770 |
Mutation-specific effects of polymorphism H558R in SCN5A-related sick sinus syndrome. | Gui J | Journal of cardiovascular electrophysiology | 2010 | PMID: 20384651 |
Text-mined citations for rs1559771280 ...
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.