This missense variant replaces arginine with histidine at codon 282 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). Functional studies have shown that this variant causes a large reduction in sodium channel current due to the defect in trafficking to cell surface (PMID: 15828879, 16864729, 21840964, 35305865). This variant has been reported in at least nine unrelated individuals affected with Brugada syndrome (PMID: 11901046, 20625312, 28341781, 30662450, 32893267). This variant has been shown to segregate with disease in five individuals affected with Brugada syndrome in two families and also seen in one unaffected family member (PMID: 14607451, 15828879, 16864729). This variant has been identified in 4/249398 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.845G>A (p.Arg282His)
Germline
Classification
Help
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.
(10)
Help
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.
Pathogenic/Likely pathogenic
10
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000335.5(SCN5A):c.845G>A (p.Arg282His)
Variation ID: 68048 Accession: VCV000068048.22
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3p22.2 3: 38609823 (GRCh38) [ NCBI UCSC ] 3: 38651314 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Sep 16, 2024 May 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000335.5:c.845G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000326.2:p.Arg282His missense NM_001099404.2:c.845G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001092874.1:p.Arg282His missense NM_001099405.2:c.845G>A NP_001092875.1:p.Arg282His missense NM_001160160.2:c.845G>A NP_001153632.1:p.Arg282His missense NM_001160161.2:c.845G>A NP_001153633.1:p.Arg282His missense NM_001354701.2:c.845G>A NP_001341630.1:p.Arg282His missense NM_198056.3:c.845G>A NP_932173.1:p.Arg282His missense NC_000003.12:g.38609823C>T NC_000003.11:g.38651314C>T NG_008934.1:g.44850G>A LRG_289:g.44850G>A LRG_289t1:c.845G>A Q14524:p.Arg282His - Protein change
- R282H
- Other names
- -
- Canonical SPDI
- NC_000003.12:38609822:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
- 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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
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. |
|||
| SCN5A | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3793 | 4237 | |
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. |
|---|---|---|---|---|
| Likely pathogenic (2) |
criteria provided, single submitter
|
Dec 15, 2023 | RCV000058851.17 | |
| not provided (1) |
no classification provided
|
- | RCV000144028.11 | |
| Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
May 1, 2024 | RCV001552667.21 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 20, 2022 | RCV002444522.10 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Dec 5, 2023 | RCV003591675.2 |
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
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Jun 09, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002502697.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: yes
|
|
|
Likely Pathogenic
(Dec 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Brugada syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004843402.1
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)
|
Comment:
This missense variant replaces arginine with histidine at codon 282 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces arginine with histidine at codon 282 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). Functional studies have shown that this variant causes a large reduction in sodium channel current due to the defect in trafficking to cell surface (PMID: 15828879, 16864729, 21840964, 35305865). This variant has been reported in at least nine unrelated individuals affected with Brugada syndrome (PMID: 11901046, 20625312, 28341781, 30662450, 32893267). This variant has been shown to segregate with disease in five individuals affected with Brugada syndrome in two families and also seen in one unaffected family member (PMID: 14607451, 15828879, 16864729). This variant has been identified in 4/249398 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
Number of individuals with the variant: 1
Zygosity: Single Heterozygote
|
|
|
Pathogenic
(Oct 02, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005198176.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
|
|
Likely pathogenic
(May 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001773398.5
First in ClinVar: Aug 07, 2021 Last updated: Sep 16, 2024 |
Comment:
Published functional studies demonstrate a damaging effect as this variant results in significant reduction of sodium current density in SCN5A channels (PMID: 15828879, 16864729, 21840964); … (more)
Published functional studies demonstrate a damaging effect as this variant results in significant reduction of sodium current density in SCN5A channels (PMID: 15828879, 16864729, 21840964); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27153395, 15828879, 21840964, 22581653, 28341781, 30662450, 20625312, 32893267, 11901046, 29574140, 36204818, 36516610, 33131149, 30203441, 31440721, 35305865, 16864729) (less)
|
|
|
Likely pathogenic
(Nov 27, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002019139.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jan 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001226655.4
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 68048). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that … (more)
ClinVar contains an entry for this variant (Variation ID: 68048). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SCN5A function (PMID: 15828879, 16864729). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This missense change has been observed in individuals with Brugada syndrome (PMID: 11901046, 15828879, 28341781). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs199473083, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 282 of the SCN5A protein (p.Arg282His). (less)
|
|
|
Likely pathogenic
(Dec 05, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiac arrhythmia
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV004362230.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with histidine at codon 282 of the SCN5A protein. This variant is found within the highly conserved pore-forming region of … (more)
This missense variant replaces arginine with histidine at codon 282 of the SCN5A protein. This variant is found within the highly conserved pore-forming region of transmembrane domain DI (a.a. 277-389). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with Brugada syndrome and long QT syndrome (PMID: 32893267). Functional studies have shown that this variant causes a large reduction in sodium channel current due to the defect in trafficking to cell surface (PMID: 15828879, 16864729, 21840964, 35305865). This variant has been reported in at least nine unrelated individuals affected with Brugada syndrome (PMID: 11901046, 20625312, 28341781, 30662450, 32893267). This variant has been shown to segregate with disease in five individuals affected with Brugada syndrome in two families and also seen in one unaffected family member (PMID: 14607451, 15828879, 16864729). This variant has also been reported in an individual affected with dilated cardiomyopathy (PMID: 29095814) and in another individual affected with fever-induced Brugada syndrome (PMID: 36516610). This variant has been identified in 4/249398 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
|
|
|
Pathogenic
(Jan 20, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002680777.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.845G>A (p.R282H) alteration is located in exon 7 (coding exon 6) of the SCN5A gene. This alteration results from a G to A substitution … (more)
The c.845G>A (p.R282H) alteration is located in exon 7 (coding exon 6) of the SCN5A gene. This alteration results from a G to A substitution at nucleotide position 845, causing the arginine (R) at amino acid position 282 to be replaced by a histidine (H). Based on data from gnomAD, the A allele has an overall frequency of 0.0016% (4/249398) total alleles studied. The highest observed frequency was 0.0056% (1/17976) of East Asian alleles. This alteration has been reported in several individuals with Brugada syndrome (Priori, 2002; Itoh, 2005; Poelzing, 2006; Pitzalis, 2003; Sonoda, 2018; Yamagata, 2017). Additionally, some studies have suggested co-occurrence with a different SCN5A alteration (H558R), a common polymorphism, may rescue the function of the mutant channel protein, which may partially account for the reduced penetrance observed for the variant in disease (Poelzing, 2006; Shinlapawittayatorn, 2011). This amino acid position is highly conserved in available vertebrate species. In vitro functional studies have demonstrated the alteration has a deleterious impact on sodium channel function (Itoh, 2005; Poelzing, 2006). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Brugada syndrome
Affected status: unknown
Allele origin:
germline
|
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust
Accession: SCV000090371.3
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:11901046;PMID:15828879;PMID:21840964). 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:11901046;PMID:15828879;PMID:21840964). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. (less)
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Brugada syndrome 1
Affected status: yes
Allele origin:
germline
|
GeneReviews
Accession: SCV000188921.3
First in ClinVar: Sep 11, 2014 Last updated: Oct 01, 2022 |
|
Comment:
Comment:
Published functional studies demonstrate a damaging effect as this variant results in significant reduction of sodium current density in SCN5A channels (PMID: 15828879, 16864729, 21840964); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27153395, 15828879, 21840964, 22581653, 28341781, 30662450, 20625312, 32893267, 11901046, 29574140, 36204818, 36516610, 33131149, 30203441, 31440721, 35305865, 16864729)
Comment:
ClinVar contains an entry for this variant (Variation ID: 68048). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SCN5A function (PMID: 15828879, 16864729). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This missense change has been observed in individuals with Brugada syndrome (PMID: 11901046, 15828879, 28341781). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs199473083, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 282 of the SCN5A protein (p.Arg282His).
Comment:
This missense variant replaces arginine with histidine at codon 282 of the SCN5A protein. This variant is found within the highly conserved pore-forming region of transmembrane domain DI (a.a. 277-389). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with Brugada syndrome and long QT syndrome (PMID: 32893267). Functional studies have shown that this variant causes a large reduction in sodium channel current due to the defect in trafficking to cell surface (PMID: 15828879, 16864729, 21840964, 35305865). This variant has been reported in at least nine unrelated individuals affected with Brugada syndrome (PMID: 11901046, 20625312, 28341781, 30662450, 32893267). This variant has been shown to segregate with disease in five individuals affected with Brugada syndrome in two families and also seen in one unaffected family member (PMID: 14607451, 15828879, 16864729). This variant has also been reported in an individual affected with dilated cardiomyopathy (PMID: 29095814) and in another individual affected with fever-induced Brugada syndrome (PMID: 36516610). This variant has been identified in 4/249398 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Comment:
The c.845G>A (p.R282H) alteration is located in exon 7 (coding exon 6) of the SCN5A gene. This alteration results from a G to A substitution at nucleotide position 845, causing the arginine (R) at amino acid position 282 to be replaced by a histidine (H). Based on data from gnomAD, the A allele has an overall frequency of 0.0016% (4/249398) total alleles studied. The highest observed frequency was 0.0056% (1/17976) of East Asian alleles. This alteration has been reported in several individuals with Brugada syndrome (Priori, 2002; Itoh, 2005; Poelzing, 2006; Pitzalis, 2003; Sonoda, 2018; Yamagata, 2017). Additionally, some studies have suggested co-occurrence with a different SCN5A alteration (H558R), a common polymorphism, may rescue the function of the mutant channel protein, which may partially account for the reduced penetrance observed for the variant in disease (Poelzing, 2006; Shinlapawittayatorn, 2011). This amino acid position is highly conserved in available vertebrate species. In vitro functional studies have demonstrated the alteration has a deleterious impact on sodium channel function (Itoh, 2005; Poelzing, 2006). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Comment:
This variant has been reported as associated with Brugada syndrome in the following publications (PMID:11901046;PMID:15828879;PMID:21840964). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
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. |
Comment:
This missense variant replaces arginine with histidine at codon 282 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). Functional studies have shown that this variant causes a large reduction in sodium channel current due to the defect in trafficking to cell surface (PMID: 15828879, 16864729, 21840964, 35305865). This variant has been reported in at least nine unrelated individuals affected with Brugada syndrome (PMID: 11901046, 20625312, 28341781, 30662450, 32893267). This variant has been shown to segregate with disease in five individuals affected with Brugada syndrome in two families and also seen in one unaffected family member (PMID: 14607451, 15828879, 16864729). This variant has been identified in 4/249398 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Comment:
Published functional studies demonstrate a damaging effect as this variant results in significant reduction of sodium current density in SCN5A channels (PMID: 15828879, 16864729, 21840964); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27153395, 15828879, 21840964, 22581653, 28341781, 30662450, 20625312, 32893267, 11901046, 29574140, 36204818, 36516610, 33131149, 30203441, 31440721, 35305865, 16864729)
Comment:
ClinVar contains an entry for this variant (Variation ID: 68048). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SCN5A function (PMID: 15828879, 16864729). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This missense change has been observed in individuals with Brugada syndrome (PMID: 11901046, 15828879, 28341781). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs199473083, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 282 of the SCN5A protein (p.Arg282His).
Comment:
This missense variant replaces arginine with histidine at codon 282 of the SCN5A protein. This variant is found within the highly conserved pore-forming region of transmembrane domain DI (a.a. 277-389). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with Brugada syndrome and long QT syndrome (PMID: 32893267). Functional studies have shown that this variant causes a large reduction in sodium channel current due to the defect in trafficking to cell surface (PMID: 15828879, 16864729, 21840964, 35305865). This variant has been reported in at least nine unrelated individuals affected with Brugada syndrome (PMID: 11901046, 20625312, 28341781, 30662450, 32893267). This variant has been shown to segregate with disease in five individuals affected with Brugada syndrome in two families and also seen in one unaffected family member (PMID: 14607451, 15828879, 16864729). This variant has also been reported in an individual affected with dilated cardiomyopathy (PMID: 29095814) and in another individual affected with fever-induced Brugada syndrome (PMID: 36516610). This variant has been identified in 4/249398 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Comment:
The c.845G>A (p.R282H) alteration is located in exon 7 (coding exon 6) of the SCN5A gene. This alteration results from a G to A substitution at nucleotide position 845, causing the arginine (R) at amino acid position 282 to be replaced by a histidine (H). Based on data from gnomAD, the A allele has an overall frequency of 0.0016% (4/249398) total alleles studied. The highest observed frequency was 0.0056% (1/17976) of East Asian alleles. This alteration has been reported in several individuals with Brugada syndrome (Priori, 2002; Itoh, 2005; Poelzing, 2006; Pitzalis, 2003; Sonoda, 2018; Yamagata, 2017). Additionally, some studies have suggested co-occurrence with a different SCN5A alteration (H558R), a common polymorphism, may rescue the function of the mutant channel protein, which may partially account for the reduced penetrance observed for the variant in disease (Poelzing, 2006; Shinlapawittayatorn, 2011). This amino acid position is highly conserved in available vertebrate species. In vitro functional studies have demonstrated the alteration has a deleterious impact on sodium channel function (Itoh, 2005; Poelzing, 2006). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Comment:
This variant has been reported as associated with Brugada syndrome in the following publications (PMID:11901046;PMID:15828879;PMID:21840964). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinical characteristics and electrophysiologic properties of SCN5A variants in fever-induced Brugada syndrome. | Chen GX | EBioMedicine | 2023 | PMID: 36516610 |
| Dominant negative effects of SCN5A missense variants. | O'Neill MJ | Genetics in medicine : official journal of the American College of Medical Genetics | 2022 | PMID: 35305865 |
| Brugada Syndrome. | Adam MP | - | 2022 | PMID: 20301690 |
| 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 |
| Relationship between sodium channel function and clinical phenotype in SCN5A variants associated with Brugada syndrome. | Pearman CM | Human mutation | 2020 | PMID: 33131149 |
| Impact of Ancestral Differences and Reassessment of the Classification of Previously Reported Pathogenic Variants in Patients With Brugada Syndrome in the Genomic Era: A SADS-TW BrS Registry. | Chen CJ | Frontiers in genetics | 2019 | PMID: 30662450 |
| Copy number variations of SCN5A in Brugada syndrome. | Sonoda K | Heart rhythm | 2018 | PMID: 29574140 |
| Proband-only medical exome sequencing as a cost-effective first-tier genetic diagnostic test for patients without prior molecular tests and clinical diagnosis in a developing country: the China experience. | Hu X | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 29095814 |
| 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 |
| Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer. | Maxwell KN | American journal of human genetics | 2016 | PMID: 27153395 |
| A novel strategy using cardiac sodium channel polymorphic fragments to rescue trafficking-deficient SCN5A mutations. | Shinlapawittayatorn K | Circulation. Cardiovascular genetics | 2011 | PMID: 21840964 |
| Efficacy of low-dose bepridil for prevention of ventricular fibrillation in patients with Brugada syndrome with and without SCN5A mutation. | Murakami M | Journal of cardiovascular pharmacology | 2010 | PMID: 20625312 |
| SCN5A polymorphism restores trafficking of a Brugada syndrome mutation on a separate gene. | Poelzing S | Circulation | 2006 | PMID: 16864729 |
| Clinical and electrophysiological characteristics of Brugada syndrome caused by a missense mutation in the S5-pore site of SCN5A. | Itoh H | Journal of cardiovascular electrophysiology | 2005 | PMID: 15828879 |
| QT-interval prolongation in right precordial leads: an additional electrocardiographic hallmark of Brugada syndrome. | Pitzalis MV | Journal of the American College of Cardiology | 2003 | PMID: 14607451 |
| Natural history of Brugada syndrome: insights for risk stratification and management. | Priori SG | Circulation | 2002 | PMID: 11901046 |
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Text-mined citations for rs199473083 ...
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Record last updated Nov 30, 2024
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