ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.1603C>T (p.Arg535Ter)
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
-
NM_000335.5(SCN5A):c.1603C>T (p.Arg535Ter)
Variation ID: 517279 Accession: VCV000517279.25
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3p22.2 3: 38603999 (GRCh38) [ NCBI UCSC ] 3: 38645490 (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 Apr 9, 2018 Feb 14, 2024 Jan 4, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000335.5:c.1603C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000326.2:p.Arg535Ter nonsense NM_001099404.2:c.1603C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001092874.1:p.Arg535Ter nonsense NM_001099405.2:c.1603C>T NP_001092875.1:p.Arg535Ter nonsense NM_001160160.2:c.1603C>T NP_001153632.1:p.Arg535Ter nonsense NM_001160161.2:c.1603C>T NP_001153633.1:p.Arg535Ter nonsense NM_001354701.2:c.1603C>T NP_001341630.1:p.Arg535Ter nonsense NM_198056.3:c.1603C>T NP_932173.1:p.Arg535Ter nonsense NC_000003.12:g.38603999G>A NC_000003.11:g.38645490G>A NG_008934.1:g.50674C>T LRG_289:g.50674C>T LRG_289t1:c.1603C>T LRG_289p1:p.Arg535Ter - Protein change
- R535*
- Other names
- -
- Canonical SPDI
- NC_000003.12:38603998:G:A
-
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.
The Genome Aggregation Database (gnomAD), exomes 0.00000
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 |
3555 | 3959 |
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. |
---|---|---|---|---|
Pathogenic (1) |
criteria provided, multiple submitters, no conflicts
|
Jul 6, 2018 | RCV000610147.19 | |
Pathogenic (1) |
criteria provided, single submitter
|
Dec 10, 2018 | RCV000617180.10 | |
Pathogenic (1) |
criteria provided, single submitter
|
- | RCV000845417.10 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 4, 2024 | RCV001008643.13 | |
Pathogenic (1) |
criteria provided, single submitter
|
Oct 3, 2023 | RCV001841781.11 | |
Pathogenic (1) |
criteria provided, single submitter
|
Mar 20, 2023 | RCV003314626.8 |
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. |
|
---|---|---|---|---|---|
Pathogenic
(Jul 06, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Brugada syndrome
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000731482.2
First in ClinVar: Apr 09, 2018 Last updated: Aug 26, 2019 |
Comment:
The p.Arg535X variant in SCN5A has been reported in at least 9 individuals (8 w ith Brugada syndrome and 1 referred for Long QT syndrome … (more)
The p.Arg535X variant in SCN5A has been reported in at least 9 individuals (8 w ith Brugada syndrome and 1 referred for Long QT syndrome testing), and segregate d with disease in 4 affected relatives from 1 family (Smits 2002, Keller 2005, P robst 2009, Meregalli 2009, Kapplinger 2010, Lieve 2013). This variant has been reported in ClinVar (variation ID: 517279) and has been identified in 1/17212 Ea st Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.b roadinstitute.org/). This nonsense variant leads to a premature termination codo n at position 535, which leads to a truncated protein that lacks WT function as shown by in vitro studies (Keller 2005). Heterozygous loss of function variants in the SCN5A gene have been reported in individuals with Brugada syndrome (Kappl inger 2010), DCM (Olson 2005), ventricular fibrillation (Chen 1998), as well as AV block and cardiac conduction defects (Baruteau 2012). In summary, this varian t meets criteria to be classified as pathogenic for Brugada syndrome in an autos omal dominant manner based upon segregation studies, presence in affected indivi duals and, functional evidence. ACMG/AMP criteria applied: PVS1, PM2, PS4_Modera te, PP1 (Richards 2015). (less)
Number of individuals with the variant: 4
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Familial dilated cardiomyopathy
Affected status: yes
Allele origin:
germline
|
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000987486.1
First in ClinVar: Sep 08, 2019 Last updated: Sep 08, 2019 |
|
|
Pathogenic
(May 07, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002503542.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 2
Secondary finding: no
|
|
Pathogenic
(Dec 10, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000738079.4
First in ClinVar: Apr 14, 2018 Last updated: Nov 29, 2022 |
Comment:
The p.R535* pathogenic mutation (also known as c.1603C>T), located in coding exon 11 of the SCN5A gene, results from a C to T substitution at … (more)
The p.R535* pathogenic mutation (also known as c.1603C>T), located in coding exon 11 of the SCN5A gene, results from a C to T substitution at nucleotide position 1603. This changes the amino acid from an arginine to a stop codon within coding exon 11. This alteration has been reported in several Brugada syndrome (BrS) cohorts and has been shown to segregate with disease in one family (Probst V et al. Circ Cardiovasc Genet. 2009;2:552-7; Kapplinger JD et al. Heart Rhythm. 2010;7:33-46). It has also been detected in long QT syndrome (LQTS) and sudden infant death syndrome (SIDS) cohorts (Lieve KV et al. Genet Test Mol Biomarkers. 2013;17:553-61; Winkel BG et al. Heart Rhythm. 2015;12:1241-9). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
|
|
Pathogenic
(Oct 25, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001168417.3
First in ClinVar: Mar 16, 2020 Last updated: Mar 04, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect on channel function (Keller et al., 2005); Not observed at significant frequency in large population cohorts (gnomAD); Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 517279; ClinVar); This variant is associated with the following publications: (PMID: 19606473, 23631430, 25525159, 19251209, 20129283, 28482396, 31043699, 30193851, 31447099, 33131149, 20031634, 15890323, 30662450, 34135346, 33087929, 12106943) (less)
|
|
Pathogenic
(Mar 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
SCN5A-Related Disorders
Affected status: unknown
Allele origin:
unknown
|
Illumina Laboratory Services, Illumina
Accession: SCV004014731.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
The SCN5A c.1603C>T (p.Arg535Ter) nonsense variant results in the substitution of arginine at amino acid position 535 with a stop codon. Loss of normal protein … (more)
The SCN5A c.1603C>T (p.Arg535Ter) nonsense variant results in the substitution of arginine at amino acid position 535 with a stop codon. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. Across a selection of the available literature, this variant has been identified in at least ten unrelated individuals - seven with Brugada syndrome, and one each with long QT syndrome, sudden infant death syndrome, and sudden adult cardiac death (PMID: 12106943; PMID: 15890323; PMID: 20031634; PMID: 20129283; PMID: 23631430; PMID: 25757662; PMID: 34076677). Segregation of the variant with the disorder was noted in at least one family (PMID: 20031634). This variant is reported in the Genome Aggregation Database in one allele at a frequency of 0.000056 in the East Asian population (version 2.1.1). Based on the available evidence, the c.1603C>T (p.Arg535Ter) variant is classified as pathogenic for SCN5A-related disorders. (less)
|
|
Pathogenic
(Jan 04, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000816703.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg535*) in the SCN5A gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg535*) in the SCN5A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SCN5A are known to be pathogenic (PMID: 20129283, 22789973). This variant is present in population databases (no rsID available, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with SCN5A-related arrhythmia (PMID: 12106943, 20129283, 23631430). ClinVar contains an entry for this variant (Variation ID: 517279). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Oct 03, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiac arrhythmia
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV001733982.2
First in ClinVar: Jun 19, 2021 Last updated: Feb 14, 2024 |
Comment:
This variant changes 1 nucleotide in exon 12 of the SCN5A gene, creating a premature translation stop signal. A functional study has shown that this … (more)
This variant changes 1 nucleotide in exon 12 of the SCN5A gene, creating a premature translation stop signal. A functional study has shown that this variant results in a truncated protein and leads to a complete loss of sodium current (PMID: 15890323). This variant has been reported in over ten individuals affected with Brugada syndrome (PMID: 12106943, 15890323, 16643399, 19251209, 20031634, 32893267, 35331424) or suspected of having Brugada syndrome (PMID: 20129283, 35352813), and in an individual affected with sudden infant death syndrome (PMID: 25757662). This variant has been identified in 1/247858 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of SCN5A function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
|
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 |
---|---|---|---|---|
Importance of genetic testing in unexplained cardiac arrest. | Grondin S | European heart journal | 2022 | PMID: 35352813 |
Association Between Deleterious SCN5A Variants and Ventricular Septal Defect in Young Patients With Brugada Syndrome. | Suzuki K | JACC. Clinical electrophysiology | 2022 | PMID: 35331424 |
Genetic Variants Associated With Unexplained Sudden Cardiac Death in Adult White and African American Individuals. | Guo L | JAMA cardiology | 2021 | PMID: 34076677 |
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 |
Reappraisal of variants previously linked with sudden infant death syndrome: results from three population-based cohorts. | Paludan-Müller C | European journal of human genetics : EJHG | 2019 | PMID: 31043699 |
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 |
[Identification of an SCN5A mutation in a Chinese pedigree with a history of syncope]. | Wang J | Zhonghua er ke za zhi = Chinese journal of pediatrics | 2017 | PMID: 28482396 |
The role of the sodium current complex in a nonreferred nationwide cohort of sudden infant death syndrome. | Winkel BG | Heart rhythm | 2015 | PMID: 25757662 |
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
Results of genetic testing in 855 consecutive unrelated patients referred for long QT syndrome in a clinical laboratory. | Lieve KV | Genetic testing and molecular biomarkers | 2013 | PMID: 23631430 |
Brugada syndrome 2012. | Berne P | Circulation journal : official journal of the Japanese Circulation Society | 2012 | PMID: 22789973 |
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 |
SCN5A mutations and the role of genetic background in the pathophysiology of Brugada syndrome. | Probst V | Circulation. Cardiovascular genetics | 2009 | PMID: 20031634 |
Type of SCN5A mutation determines clinical severity and degree of conduction slowing in loss-of-function sodium channelopathies. | Meregalli PG | Heart rhythm | 2009 | PMID: 19251209 |
Progressive cardiac conduction defect is the prevailing phenotype in carriers of a Brugada syndrome SCN5A mutation. | Probst V | Journal of cardiovascular electrophysiology | 2006 | PMID: 16643399 |
Brugada syndrome and fever: genetic and molecular characterization of patients carrying SCN5A mutations. | Keller DI | Cardiovascular research | 2005 | PMID: 15890323 |
Genotype-phenotype relationship in Brugada syndrome: electrocardiographic features differentiate SCN5A-related patients from non-SCN5A-related patients. | Smits JP | Journal of the American College of Cardiology | 2002 | PMID: 12106943 |
click to load more click to collapse |
Text-mined citations for rs1417036453 ...
HelpRecord last updated Mar 23, 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.