ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.4891C>T (p.Arg1631Cys)
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.4891C>T (p.Arg1631Cys)
Variation ID: 242199 Accession: VCV000242199.7
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 38551478 (GRCh38) [ NCBI UCSC ] 3: 38592969 (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 19, 2017 Feb 20, 2024 Apr 18, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000335.5:c.4891C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000326.2:p.Arg1631Cys missense NM_001099404.2:c.4894C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001092874.1:p.Arg1632Cys missense NM_001099405.2:c.4840C>T NP_001092875.1:p.Arg1614Cys missense NM_001160160.2:c.4795C>T NP_001153632.1:p.Arg1599Cys missense NM_001160161.2:c.4732C>T NP_001153633.1:p.Arg1578Cys missense NM_001354701.2:c.4837C>T NP_001341630.1:p.Arg1613Cys missense NM_198056.3:c.4894C>T NP_932173.1:p.Arg1632Cys missense NC_000003.12:g.38551478G>A NC_000003.11:g.38592969G>A NG_008934.1:g.103195C>T LRG_289:g.103195C>T LRG_289t1:c.4894C>T LRG_289p1:p.Arg1632Cys - Protein change
- R1631C, R1632C, R1578C, R1599C, R1614C, R1613C
- Other names
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- Canonical SPDI
- NC_000003.12:38551477:G: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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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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 | - |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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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Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Apr 18, 2023 | RCV000431928.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 5, 2020 | RCV002338764.1 |
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
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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
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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
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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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Pathogenic
(Aug 23, 2017)
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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: SCV000517352.4
First in ClinVar: Mar 08, 2017 Last updated: Dec 19, 2017 |
Comment:
R1632C in the SCN5A gene has been reported in a 17-year-old male with a history of syncope afterexercise; presenting with atrial tachycardia, sinus node dysfunction … (more)
R1632C in the SCN5A gene has been reported in a 17-year-old male with a history of syncope afterexercise; presenting with atrial tachycardia, sinus node dysfunction and Brugada syndrome (Nakajima etal., 2015). R1632C was identified in the proband's mother who had a personal history of syncope andBrugada pattern on ECG after drug challenge. Additionally, R1632C was absent in 200 control alleles.R1632C is located in the DIV-S4 voltage sensor and in-vitro functional studies revealed R1632C results inenhanced fast-inactivated state stability due to delayed recovery from fast inactivation, resulting in loss ofsodium channel availability (Nakajima et la., 2015). The R1632C variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In addition, the R1632C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysispredicts this variant is probably damaging to the protein structure/function. Furthermore, several missensevariants in nearby residues (R1626P, R1626H, R1629G, R1629Q, G1631D) including one at the sameresidue (R1632H) have been reported in the Human Gene Mutation Database (HGMD) in association witharrhythmia (Stenson et al., 2014), supporting the functional importance of this region of the protein.In summary, R1632C in the SCN5A gene is interpreted as a pathogenic variant. (less)
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Pathogenic
(Sep 05, 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: SCV002635766.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.R1632C pathogenic mutation (also known as c.4894C>T), located in coding exon 27 of the SCN5A gene, results from a C to T substitution at … (more)
The p.R1632C pathogenic mutation (also known as c.4894C>T), located in coding exon 27 of the SCN5A gene, results from a C to T substitution at nucleotide position 4894. The arginine at codon 1632 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the DIV-S4 transmembrane region. This variant has been detected in unrelated probands with Brugada syndrome (BrS) and has shown some segregation with disease in families (Nakajima T et al. Heart Rhythm, 2015 Nov;12:2296-304; García-Molina E et al. Mol Med Rep, 2016 Jun;13:4677-80; Monasky MM et al. Front Physiol, 2019 May;10:666). Internal structural analysis indicates that the arginine impacted by this alteration is part of a highly conserved set of residues that generate a characteristic motif necessary to the function of voltage-sensing channels (Gandhi CS et al. J. Gen. Physiol., 2002 Oct;120:455-63; Starace DM et al. Nature, 2004 Feb;427:548-53). In vitro functional studies have indicated that this variant may impact channel kinetics, and a deep mutational scanning study categorized this alteration as a possible loss of function alteration (Nakajima T et al. Heart Rhythm, 2015 Nov;12:2296-304; Glazer AM et al. Circ Genom Precis Med, 2020 02;13:e002786). Other variants affecting this codon (p.R1632H, c.4895G>A and p.R1632L, c.4895G>T) have also been reported in association with arrhythmias, including Brugada syndrome (Benson DW et al. J. Clin. Invest. 2003;112:1019-28; Batchvarov VN et al. J Electrocardiol;44:308). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Apr 18, 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: SCV000291812.7
First in ClinVar: Jul 01, 2016 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SCN5A function (PMID: 26031372). An algorithm … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SCN5A function (PMID: 26031372). 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: 242199). This missense change has been observed in individuals with Brugada syndrome (PMID: 26031372, 27082542, 31191357). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1632 of the SCN5A protein (p.Arg1632Cys). (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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Deep Mutational Scan of an SCN5A Voltage Sensor. | Glazer AM | Circulation. Genomic and precision medicine | 2020 | PMID: 31928070 |
Genotype/Phenotype Relationship in a Consanguineal Family With Brugada Syndrome Harboring the R1632C Missense Variant in the SCN5A Gene. | Monasky MM | Frontiers in physiology | 2019 | PMID: 31191357 |
Enhanced closed-state inactivation of mutant cardiac sodium channels (SCN5A N1541D and R1632C) through different mechanisms. | Dharmawan T | Journal of molecular and cellular cardiology | 2019 | PMID: 30935997 |
An R1632C variant in the SCN5A gene causing Brugada syndrome. | García-Molina E | Molecular medicine reports | 2016 | PMID: 27082542 |
Text-mined citations for rs878855292 ...
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.