ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.361C>T (p.Arg121Trp)
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.361C>T (p.Arg121Trp)
Variation ID: 67807 Accession: VCV000067807.14
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3p22.2 3: 38630342 (GRCh38) [ NCBI UCSC ] 3: 38671833 (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 May 1, 2024 Aug 2, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000335.5:c.361C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000326.2:p.Arg121Trp missense NM_001099404.2:c.361C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001092874.1:p.Arg121Trp missense NM_001099405.2:c.361C>T NP_001092875.1:p.Arg121Trp missense NM_001160160.2:c.361C>T NP_001153632.1:p.Arg121Trp missense NM_001160161.2:c.361C>T NP_001153633.1:p.Arg121Trp missense NM_001354701.2:c.361C>T NP_001341630.1:p.Arg121Trp missense NM_198056.3:c.361C>T NP_932173.1:p.Arg121Trp missense NC_000003.12:g.38630342G>A NC_000003.11:g.38671833G>A NG_008934.1:g.24331C>T LRG_289:g.24331C>T LRG_289t1:c.361C>T LRG_289p1:p.Arg121Trp Q14524:p.Arg121Trp - Protein change
- R121W
- Other names
- -
- Canonical SPDI
- NC_000003.12:38630341: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.
-
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 |
3779 | 4220 |
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. |
---|---|---|---|---|
not provided (1) |
criteria provided, single submitter
|
- | RCV000058582.8 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Aug 2, 2023 | RCV000413145.5 | |
Pathogenic (1) |
criteria provided, single submitter
|
May 24, 2017 | RCV000522231.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Sep 1, 2017 | RCV000622117.3 |
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 16, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000490788.3
First in ClinVar: Jan 09, 2017 Last updated: Jul 24, 2021 |
Comment:
Identified in at least two unrelated individuals with Brugada syndrome in published literature (Kapplinger et al., 2010; Selga et al., 2015); Identified in a patient … (more)
Identified in at least two unrelated individuals with Brugada syndrome in published literature (Kapplinger et al., 2010; Selga et al., 2015); Identified in a patient with arrhythmia and was also identified in his father who had a milder phenotype (Holst et al., 2010); Identified in a patient with sudden arrhythmic death syndrome (SADS) who had no cardiac symptoms prior to death and was also identified in his mother and brother who showed Brugada pattern on electrocardiogram (Lahrouchi et al., 2017); Not observed in large population cohorts (Lek et al., 2016); Reported as pathogenic/likely pathogenic in ClinVar but additional evidence is not available (ClinVar Variant ID#67807; Landrum et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a significant reduction of sodium current and reduced amounts of sodium channels (Holst et al., 2010; Clatot et al., 2012); A different missense change at this residue (R121Q) has been reported as pathogenic in ClinVar (ClinVar SCV#67808; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 31737537, 26173111, 28449774, 20395683, 22739120, 23874304, 20129283, 25863800, 23123192, 19606473, 24136861, 25904541, 30662450) (less)
|
|
Likely pathogenic
(Sep 01, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000738156.5
First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024 |
Comment:
The p.R121W variant (also known as c.361C>T), located in coding exon 2 of the SCN5A gene, results from a C to T substitution at nucleotide … (more)
The p.R121W variant (also known as c.361C>T), located in coding exon 2 of the SCN5A gene, results from a C to T substitution at nucleotide position 361. The arginine at codon 121 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in association with Brugada syndrome (Kapplinger JD et al. Heart Rhythm, 2010 Jan;7:33-46; Hertz CL et al. Int. J. Legal Med., 2015 Jul;129:793-800; Leong KM et al. HeartRhythm Case Rep, 2017 Mar;3:167-171). This alteration was also reported in a proband and his father who both had cardiac conduction disease (Holst AG et al. Cardiology, 2010 Apr;115:311-6). In addition, functional studies demonstrate a reduction of sodium current and are consistent with a dominant negative effect through retention in the endoplasmic reticulum (Holst AG et al. Cardiology, 2010 Apr;115:311-6; Clatot J et al. Cardiovasc. Res., 2012 Oct;96:53-63). 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)
|
|
Pathogenic
(May 24, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Brugada syndrome 1
Affected status: yes
Allele origin:
unknown
|
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues
Accession: SCV000616616.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
|
|
Pathogenic
(Aug 02, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000820708.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg121 amino acid residue in SCN5A. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg121 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20129283, 24529773). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects SCN5A function (PMID: 20395683, 22739120). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 32533946) indicates that this missense variant is expected to disrupt SCN5A function. ClinVar contains an entry for this variant (Variation ID: 67807). This missense change has been observed in individuals with Brugada syndrome (PMID: 19606473, 20129283, 20395683, 24136861, 26173111, 28449774). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 121 of the SCN5A protein (p.Arg121Trp). (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: SCV000090102.3
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:19606473;PMID:20129283;PMID:20395683;PMID:22739120). 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:19606473;PMID:20129283;PMID:20395683;PMID:22739120). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. (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 |
---|---|---|---|---|
High-Throughput Reclassification of SCN5A Variants. | Glazer AM | American journal of human genetics | 2020 | PMID: 32533946 |
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 |
Proarrhythmogenic effects of lamotrigine during ajmaline testing for Brugada syndrome. | Leong KM | HeartRhythm case reports | 2017 | PMID: 28344931 |
Comprehensive Genetic Characterization of a Spanish Brugada Syndrome Cohort. | Selga E | PloS one | 2015 | PMID: 26173111 |
Next-generation sequencing of 34 genes in sudden unexplained death victims in forensics and in patients with channelopathic cardiac diseases. | Hertz CL | International journal of legal medicine | 2015 | PMID: 25467552 |
Is sudden unexplained nocturnal death syndrome in Southern China a cardiac sodium channel dysfunction disorder? | Liu C | Forensic science international | 2014 | PMID: 24529773 |
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 |
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 |
Sick sinus syndrome, progressive cardiac conduction disease, atrial flutter and ventricular tachycardia caused by a novel SCN5A mutation. | Holst AG | Cardiology | 2010 | PMID: 20395683 |
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 |
The genetic basis of Brugada syndrome: a mutation update. | Hedley PL | Human mutation | 2009 | PMID: 19606473 |
click to load more click to collapse |
Text-mined citations for rs199473556 ...
HelpRecord last updated Sep 29, 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.