ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.2632C>T (p.Arg878Cys)
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.2632C>T (p.Arg878Cys)
Variation ID: 67744 Accession: VCV000067744.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 38585846 (GRCh38) [ NCBI UCSC ] 3: 38627337 (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 Feb 14, 2024 Dec 14, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000335.5:c.2632C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000326.2:p.Arg878Cys missense NM_001099404.2:c.2632C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001092874.1:p.Arg878Cys missense NM_001099405.2:c.2632C>T NP_001092875.1:p.Arg878Cys missense NM_001160160.2:c.2632C>T NP_001153632.1:p.Arg878Cys missense NM_001160161.2:c.2632C>T NP_001153633.1:p.Arg878Cys missense NM_001354701.2:c.2632C>T NP_001341630.1:p.Arg878Cys missense NM_198056.3:c.2632C>T NP_932173.1:p.Arg878Cys missense NC_000003.12:g.38585846G>A NC_000003.11:g.38627337G>A NG_008934.1:g.68827C>T LRG_289:g.68827C>T LRG_289t1:c.2632C>T LRG_289p1:p.Arg878Cys Q14524:p.Arg878Cys - Protein change
- R878C
- Other names
- p.R878C:CGC>TGC
- Canonical SPDI
- NC_000003.12:38585845: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.
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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
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 |
3554 | 3958 |
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
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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- | RCV000058513.6 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 14, 2023 | RCV000183008.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Aug 9, 2018 | RCV000621112.2 |
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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Likely pathogenic
(Jul 28, 2020)
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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: SCV000235414.12
First in ClinVar: Jul 05, 2015 Last updated: May 29, 2016 |
Comment:
Reported to segregate with varying arrhythmia phenotypes in four individuals from one family (Zhang et al., 2008); Not observed in large population cohorts (Lek et … (more)
Reported to segregate with varying arrhythmia phenotypes in four individuals from one family (Zhang et al., 2008); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 67744; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 22840528, 28449774, 18616619, 20539757, 27381756, 20960617, 24136861, 17368591, 25399282, 26036855, 30476647, 29233994, 30232268, 22739120, 28781330, 28341781, 20129283, 24055942, 30662450, 33131149) (less)
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Likely pathogenic
(Aug 09, 2018)
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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: SCV000737852.4
First in ClinVar: Apr 14, 2018 Last updated: Nov 29, 2022 |
Comment:
The p.R878C variant (also known as c.2632C>T), located in coding exon 15 of the SCN5A gene, results from a C to T substitution at nucleotide … (more)
The p.R878C variant (also known as c.2632C>T), located in coding exon 15 of the SCN5A gene, results from a C to T substitution at nucleotide position 2632. The arginine at codon 878 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in individuals with Brugada syndrome and sick sinus syndrome (Savastano S et al. Heart Rhythm, 2014 Jul;11:1176-83; Crotti L et al., Hum. Genet., 2008 Jun;123:537-55; Crotti L et al. J. Am. Coll. Cardiol., 2012 Oct;60:1410-8; Kapplinger JD et al. Heart Rhythm, 2010 Jan;7:33-46; Zhang Y et al. Acta Physiol (Oxf), 2008 Dec;194:311-23). Segregation with disease has been reported in some families; however, clinical information was limited and some family members had additional variants (Crotti L et al., Hum. Genet., 2008 Jun;123:537-55; Zhang Y et al. Acta Physiol (Oxf), 2008 Dec;194:311-23; Bissay V et al. Eur. J. Hum. Genet., 2016 Mar;24:400-7; Van Malderen SCH et al. Circ. J., 2017 Dec;82:53-61). This variant is located in the S5-S6 pore-forming segment of the DII domain, and functional studies have demonstrated loss of sodium channel function despite proper localization in the cell membrane (Gui J et al. PLoS ONE, 2010 Jun;5:e10985; Zhang Y et al. Acta Physiol (Oxf), 2008 Dec;194:311-23). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(Dec 14, 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: SCV001214073.4
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 878 of the SCN5A protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 878 of the SCN5A protein (p.Arg878Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Brugada syndrome (PMID: 18616619, 20960618, 26036855, 28341781, 28781330). ClinVar contains an entry for this variant (Variation ID: 67744). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SCN5A function (PMID: 18616619, 20384651, 20539757, 22739120). This variant disrupts the p.Arg878 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20129283, 25904541, 30193851; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (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: SCV000090033.3
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:18616619;PMID:20129283;PMID:20539757;PMID:20960617). 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:18616619;PMID:20129283;PMID:20539757;PMID:20960617). 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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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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Clinical presentation and follow-up of women affected by Brugada syndrome. | Berthome P | Heart rhythm | 2019 | PMID: 30193851 |
Prolonged Right Ventricular Ejection Delay in Brugada Syndrome Depends on the Type of SCN5A Variant - Electromechanical Coupling Through Tissue Velocity Imaging as a Bridge Between Genotyping and Phenotyping. | Van Malderen SCH | Circulation journal : official journal of the Japanese Circulation Society | 2017 | PMID: 28781330 |
Utility of Post-Mortem Genetic Testing in Cases of Sudden Arrhythmic Death Syndrome. | Lahrouchi N | Journal of the American College of Cardiology | 2017 | PMID: 28449774 |
Genotype-Phenotype Correlation of SCN5A Mutation for the Clinical and Electrocardiographic Characteristics of Probands With Brugada Syndrome: A Japanese Multicenter Registry. | Yamagata K | Circulation | 2017 | PMID: 28341781 |
SCN4A variants and Brugada syndrome: phenotypic and genotypic overlap between cardiac and skeletal muscle sodium channelopathies. | Bissay V | European journal of human genetics : EJHG | 2016 | PMID: 26036855 |
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 |
A comprehensive electrocardiographic, molecular, and echocardiographic study of Brugada syndrome: validation of the 2013 diagnostic criteria. | Savastano S | Heart rhythm | 2014 | PMID: 24721456 |
Spectrum and prevalence of mutations involving BrS1- through BrS12-susceptibility genes in a cohort of unrelated patients referred for Brugada syndrome genetic testing: implications for genetic testing. | Crotti L | Journal of the American College of Cardiology | 2012 | PMID: 22840528 |
Dominant-negative effect of SCN5A N-terminal mutations through the interaction of Na(v)1.5 α-subunits. | Clatot J | Cardiovascular research | 2012 | PMID: 22739120 |
Multiple loss-of-function mechanisms contribute to SCN5A-related familial sick sinus syndrome. | Gui J | PloS one | 2010 | PMID: 20539757 |
Mutation-specific effects of polymorphism H558R in SCN5A-related sick sinus syndrome. | Gui J | Journal of cardiovascular electrophysiology | 2010 | PMID: 20384651 |
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 |
Gene symbol: SCN5A. Disease: Brugada syndrome. | Crotti L | Human genetics | 2008 | PMID: 20960618 |
Gene symbol: SCN5A. Disease: Brugada syndrome. | Crotti L | Human genetics | 2008 | PMID: 20960617 |
Correlations between clinical and physiological consequences of the novel mutation R878C in a highly conserved pore residue in the cardiac Na+ channel. | Zhang Y | Acta physiologica (Oxford, England) | 2008 | PMID: 18616619 |
Novel human pathological mutations. | - | Human genetics | 2008 | PMID: 18465145 |
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Text-mined citations for rs199473168 ...
HelpRecord last updated Feb 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.