ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.5371G>A (p.Asp1791Asn)
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.5371G>A (p.Asp1791Asn)
Variation ID: 178858 Accession: VCV000178858.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 38550998 (GRCh38) [ NCBI UCSC ] 3: 38592489 (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, 2016 Sep 16, 2024 Feb 23, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000335.5:c.5371G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000326.2:p.Asp1791Asn missense NM_001099404.2:c.5374G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001092874.1:p.Asp1792Asn missense NM_001099405.2:c.5320G>A NP_001092875.1:p.Asp1774Asn missense NM_001160160.2:c.5275G>A NP_001153632.1:p.Asp1759Asn missense NM_001160161.2:c.5212G>A NP_001153633.1:p.Asp1738Asn missense NM_001354701.2:c.5317G>A NP_001341630.1:p.Asp1773Asn missense NM_198056.3:c.5374G>A NP_932173.1:p.Asp1792Asn missense NC_000003.12:g.38550998C>T NC_000003.11:g.38592489C>T NG_008934.1:g.103675G>A LRG_289:g.103675G>A LRG_289t1:c.5374G>A LRG_289p1:p.Asp1792Asn Q14524:p.Asp1792Asn - Protein change
- D1791N, D1792N, D1774N, D1773N, D1738N, D1759N
- Other names
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p.D1792N:GAT>AAT
- Canonical SPDI
- NC_000003.12:38550997: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.
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Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00004
- 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 | 4220 |
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 (2) |
criteria provided, multiple submitters, no conflicts
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Feb 14, 2022 | RCV000155630.17 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Feb 23, 2024 | RCV000766810.15 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Dec 13, 2023 | RCV001842486.13 |
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
(Sep 21, 2017)
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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: SCV000205338.5
First in ClinVar: Jan 31, 2015 Last updated: Apr 17, 2019 |
Comment:
proposed classification - variant undergoing re-assessment, contact laboratory
Number of individuals with the variant: 1
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Uncertain significance
(Feb 14, 2022)
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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: SCV002104126.1
First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022 |
Comment:
Variant summary: SCN5A c.5374G>A (p.Asp1792Asn) results in a conservative amino acid change located in the Carboxy terminal domain (Li_2021) of the encoded protein sequence. Four … (more)
Variant summary: SCN5A c.5374G>A (p.Asp1792Asn) results in a conservative amino acid change located in the Carboxy terminal domain (Li_2021) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250584 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5374G>A has been reported in the literature in at-least one individual affected with Cardiac sinus node dysfunction who also harbored another missense variant in SCN5A (c.2204C>T, p.Ala735Val) that has been classified as Likely Pathogenic by another clinical laboratory submitter (example, Selly_2012 and the ClinVar database). These report(s) do not provide unequivocal conclusions about association of this specific variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(May 01, 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: SCV001341526.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces aspartic acid with asparagine at codon 1792 of the SCN5A protein. Computational prediction suggests that this variant may have a deleterious … (more)
This missense variant replaces aspartic acid with asparagine at codon 1792 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 cardiac sinus node dysfunction (PMID: 22795782). This variant has been identified in 5/250584 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
(Jan 09, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000545052.4
First in ClinVar: Apr 17, 2017 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1792 of the SCN5A protein … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1792 of the SCN5A protein (p.Asp1792Asn). This variant is present in population databases (rs727504495, gnomAD 0.01%). This missense change has been observed in individual(s) with bradycardia (PMID: 22795782). ClinVar contains an entry for this variant (Variation ID: 178858). 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. 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
(Dec 13, 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: SCV004829496.1
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 aspartic acid with asparagine at codon 1792 of the SCN5A protein. Computational prediction suggests that this variant may have a deleterious … (more)
This missense variant replaces aspartic acid with asparagine at codon 1792 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 cardiac sinus node dysfunction (PMID: 22795782). This variant has been identified in 5/250584 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
(Feb 23, 2024)
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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: SCV000235530.14
First in ClinVar: Jul 05, 2015 Last updated: Sep 16, 2024 |
Comment:
Reported in a 10-year-old patient with bradycardia and cardiac sinus node dysfunction and in a patient with fever-induced Brugada syndrome; however, one of these individuals … (more)
Reported in a 10-year-old patient with bradycardia and cardiac sinus node dysfunction and in a patient with fever-induced Brugada syndrome; however, one of these individuals harbored a second variant in the SCN5A gene (PMID: 22795782, 34643236); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28150151, 32048431, 35650162, 36516610, 22795782, 34643236) (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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Structure of human Na(v)1.5 reveals the fast inactivation-related segments as a mutational hotspot for the long QT syndrome. | Li Z | Proceedings of the National Academy of Sciences of the United States of America | 2021 | PMID: 33712541 |
Critical assessment of secondary findings in genes linked to primary arrhythmia syndromes. | Diebold I | Human mutation | 2020 | PMID: 32048431 |
[Cardiac sinus node dysfunction due to a new mutation of the SCN5A gene]. | Selly JB | Archives de pediatrie : organe officiel de la Societe francaise de pediatrie | 2012 | PMID: 22795782 |
Text-mined citations for rs727504495 ...
HelpRecord last updated Oct 27, 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.