ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.4054G>A (p.Val1352Met)
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.
Uncertain significance(10); Benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000335.5(SCN5A):c.4054G>A (p.Val1352Met)
Variation ID: 67857 Accession: VCV000067857.39
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 38560335 (GRCh38) [ NCBI UCSC ] 3: 38601826 (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 9, 2014 Apr 20, 2024 Dec 18, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000335.5:c.4054G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000326.2:p.Val1352Met missense NM_001099404.2:c.4057G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001092874.1:p.Val1353Met missense NM_001099405.2:c.4057G>A NP_001092875.1:p.Val1353Met missense NM_001160160.2:c.4054G>A NP_001153632.1:p.Val1352Met missense NM_001160161.2:c.3895G>A NP_001153633.1:p.Val1299Met missense NM_001354701.2:c.4054G>A NP_001341630.1:p.Val1352Met missense NM_198056.3:c.4057G>A NP_932173.1:p.Val1353Met missense NC_000003.12:g.38560335C>T NC_000003.11:g.38601826C>T NG_008934.1:g.94338G>A LRG_289:g.94338G>A LRG_289t1:c.4057G>A LRG_289p1:p.Val1353Met Q14524:p.Val1353Met - Protein change
- V1352M, V1353M, V1299M
- Other names
- p.V1353M:GTG>ATG
- Canonical SPDI
- NC_000003.12:38560334: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) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00003
Exome Aggregation Consortium (ExAC) 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 |
3739 | 4175 |
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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- | RCV000058636.14 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Aug 4, 2023 | RCV000183060.26 | |
Benign (1) |
criteria provided, single submitter
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Apr 28, 2017 | RCV001146614.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 28, 2017 | RCV001144668.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 28, 2017 | RCV001144669.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 28, 2017 | RCV001144670.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 28, 2017 | RCV001144671.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 28, 2017 | RCV001146613.12 | |
not provided (1) |
no classification provided
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- | RCV001535662.9 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Dec 18, 2023 | RCV001842358.12 |
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
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Brugada syndrome 1
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001305281.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Dilated cardiomyopathy 1E
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001305282.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Ventricular fibrillation, paroxysmal familial, type 1
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001305284.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome 3
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001305283.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Progressive familial heart block, type 1A
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001307364.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Benign
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Sick sinus syndrome 1
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001307365.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. (less)
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Uncertain significance
(Apr 06, 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: SCV000235469.11
First in ClinVar: Jul 05, 2015 Last updated: Dec 19, 2017 |
Comment:
Reported in association with Brugada syndrome, sudden infant death syndrome, and left ventricular dysfunction (Kapplinger et al., 2010; Neubauer et al., 2017; Hazebroek et al., … (more)
Reported in association with Brugada syndrome, sudden infant death syndrome, and left ventricular dysfunction (Kapplinger et al., 2010; Neubauer et al., 2017; Hazebroek et al., 2018); Identified in patients referred for Brugada syndrome or Long QT syndrome genetic testing at GeneDx and found to segregate with disease in one relative; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID#67857; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 30086531, 24136861, 20129283, 28074886, 26746457, 28150151, 29540472, 30662450, 31737537, 32569262, 33221895, 32533946, 32880476) (less)
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Uncertain significance
(Aug 04, 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: SCV001211979.4
First in ClinVar: Apr 15, 2020 Last updated: Feb 28, 2024 |
Comment:
This variant is present in population databases (rs199473233, gnomAD 0.006%). In summary, the available evidence is currently insufficient to determine the role of this variant … (more)
This variant is present in population databases (rs199473233, gnomAD 0.006%). 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. Experimental studies have shown that this missense change does not substantially affect SCN5A function (PMID: 32533946). 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. ClinVar contains an entry for this variant (Variation ID: 67857). This variant is also known as p.V1352M. This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 20129283, 28074886, 29540472, 30086531, 31737537, 32880476, 33221895, 33996946). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1353 of the SCN5A protein (p.Val1353Met). (less)
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Uncertain significance
(Mar 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001153862.21
First in ClinVar: Feb 03, 2020 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 2
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Uncertain Significance
(Dec 18, 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: SCV004824189.1
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 methionine at codon 1353 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces valine with methionine at codon 1353 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). This variant is found within a highly conserved region of the transmembrane domain DIII. Rare nontruncating variants in this region (a.a. 1207-1466) have been shown to be significantly overrepresented in individuals with Brugada syndrome (PMID: 32893267). A functional study has shown that this variant does not change channel peak current density in transfected cells (PMID: 32533946). This variant has been reported in at least five individuals affected with Brugada syndrome (PMID: 24136861, 33221895, 32893267, 36516610, 36724992), in four individuals suspected of having Brugada syndrome (PMID: 20129283) or long QT syndrome (PMID: 31737537, ClinVar SCV000235469.11). This variant has also been reported in individuals affected with sudden infant death syndrome (PMID: 28074886, 30086531), left ventricular dysfunction (PMID: 29540472), and dilated cardiomyopathy (PMID: 32880476). This variant has been identified in 7/251488 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion for a pathogenic role, 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: 5
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Uncertain significance
(Nov 20, 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: SCV001357584.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces valine with methionine at codon 1353 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces valine with methionine at codon 1353 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). This variant is found within a highly conserved region of the transmembrane domain DIII. Rare nontruncating variants in this region (a.a. 1207-1466) have been shown to be significantly overrepresented in individuals with Brugada syndrome (PMID: 32893267). A functional study has shown that this variant does not change channel peak current density in transfected cells (PMID: 32533946). This variant has been reported in at least five individuals affected with Brugada syndrome (PMID: 24136861, 33221895, 32893267, 36516610, 36724992), in four individuals suspected of having Brugada syndrome (PMID: 20129283) or long QT syndrome (PMID: 31737537, ClinVar SCV000235469.11). This variant has also been reported in individuals affected with sudden infant death syndrome (PMID: 28074886, 30086531), left ventricular dysfunction (PMID: 29540472), and dilated cardiomyopathy (PMID: 32880476). This variant has been identified in 7/251488 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion for a pathogenic role, 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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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: SCV000090156.3
First in ClinVar: Oct 22, 2013 Last updated: Jun 09, 2014 |
Comment:
This variant has been reported as associated with Brugada syndrome in the following publications (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: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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not provided
(-)
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no classification provided
Method: phenotyping only
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Brugada syndrome 1
Dilated cardiomyopathy 1E
Affected status: unknown
Allele origin:
unknown
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GenomeConnect - Invitae Patient Insights Network
Accession: SCV001749717.1
First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021 |
Comment:
Variant interpreted as Uncertain significance and reported on 09-11-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided … (more)
Variant interpreted as Uncertain significance and reported on 09-11-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Clinical Features:
Abnormal cardiovascular system morphology (present) , Asthma (present) , Obesity (present) , Anxiety (present) , Maternal teratogenic exposure (present)
Indication for testing: Diagnostic
Age: 30-39 years
Sex: male
Testing laboratory: Invitae
Date variant was reported to submitter: 2019-09-11
Testing laboratory interpretation: Uncertain significance
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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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Brugada syndrome and job fitness: report of three cases. | Candura SM | Industrial health | 2023 | PMID: 36724992 |
Clinical characteristics and electrophysiologic properties of SCN5A variants in fever-induced Brugada syndrome. | Chen GX | EBioMedicine | 2023 | PMID: 36516610 |
Clinical Significance of Variants in the TTN Gene in a Large Cohort of Patients With Sporadic Dilated Cardiomyopathy. | Xiao L | Frontiers in cardiovascular medicine | 2021 | PMID: 33996946 |
Brugada syndrome genetics is associated with phenotype severity. | Ciconte G | European heart journal | 2021 | PMID: 33221895 |
Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls. | Walsh R | Genetics in medicine : official journal of the American College of Medical Genetics | 2021 | PMID: 32893267 |
Implications of Genetic Testing in Dilated Cardiomyopathy. | Verdonschot JAJ | Circulation. Genomic and precision medicine | 2020 | PMID: 32880476 |
High-Throughput Reclassification of SCN5A Variants. | Glazer AM | American journal of human genetics | 2020 | PMID: 32533946 |
Variant panorama in 1,385 index patients and sensitivity of expanded next-generation sequencing panels in arrhythmogenic disorders. | Marschall C | Cardiovascular diagnosis and therapy | 2019 | PMID: 31737537 |
Molecular autopsy in a cohort of infants died suddenly at rest. | Campuzano O | Forensic science international. Genetics | 2018 | PMID: 30086531 |
Prevalence of Pathogenic Gene Mutations and Prognosis Do Not Differ in Isolated Left Ventricular Dysfunction Compared With Dilated Cardiomyopathy. | Hazebroek MR | Circulation. Heart failure | 2018 | PMID: 29540472 |
Post-mortem whole-exome analysis in a large sudden infant death syndrome cohort with a focus on cardiovascular and metabolic genetic diseases. | Neubauer J | European journal of human genetics : EJHG | 2017 | PMID: 28074886 |
Paralogue annotation identifies novel pathogenic variants in patients with Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia. | Walsh R | Journal of medical genetics | 2014 | PMID: 24136861 |
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 |
Steryl clycoside acyltransferase from carrots. | Eichenberger W | FEBS letters | 1975 | PMID: 235469 |
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Text-mined citations for rs199473233 ...
HelpRecord last updated May 01, 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.