ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.4882C>T (p.Arg1628Ter)
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.4882C>T (p.Arg1628Ter)
Variation ID: 264276 Accession: VCV000264276.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 38551487 (GRCh38) [ NCBI UCSC ] 3: 38592978 (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 Oct 3, 2016 Feb 14, 2024 Nov 10, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000335.5:c.4882C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000326.2:p.Arg1628Ter nonsense NM_001099404.2:c.4885C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001092874.1:p.Arg1629Ter nonsense NM_001099405.2:c.4831C>T NP_001092875.1:p.Arg1611Ter nonsense NM_001160160.2:c.4786C>T NP_001153632.1:p.Arg1596Ter nonsense NM_001160161.2:c.4723C>T NP_001153633.1:p.Arg1575Ter nonsense NM_001354701.2:c.4828C>T NP_001341630.1:p.Arg1610Ter nonsense NM_198056.3:c.4885C>T NP_932173.1:p.Arg1629Ter nonsense NC_000003.12:g.38551487G>A NC_000003.11:g.38592978G>A NG_008934.1:g.103186C>T LRG_289:g.103186C>T LRG_289t1:c.4885C>T LRG_289p1:p.Arg1629Ter - Protein change
- R1628*, R1629*, R1610*, R1575*, R1596*, R1611*
- Other names
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- Canonical SPDI
- NC_000003.12:38551486: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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0.00020 (A)
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
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 | ||
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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 |
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. |
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Pathogenic (1) |
criteria provided, single submitter
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Aug 31, 2018 | RCV000250943.2 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Nov 10, 2023 | RCV000442994.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 11, 2023 | RCV000987200.2 |
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. |
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Pathogenic
(Oct 27, 2019)
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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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001713283.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Comment:
PVS1_Strong, PM1, PS3_Supporting
Number of individuals with the variant: 1
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Pathogenic
(Aug 31, 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: SCV000320087.6
First in ClinVar: Oct 03, 2016 Last updated: Nov 29, 2022 |
Comment:
The p.R1629* pathogenic mutation (also known as c.4885C>T), located in coding exon 27 of the SCN5A gene, results from a C to T substitution at … (more)
The p.R1629* pathogenic mutation (also known as c.4885C>T), located in coding exon 27 of the SCN5A gene, results from a C to T substitution at nucleotide position 4885. This changes the amino acid from an arginine to a stop codon within coding exon 27. In a study of Brugada syndrome clinical genetic testing, this alteration was reported in one patient (Kapplinger JD et al. Heart Rhythm. 2010;7(1):33-46). In addition, a young adult with Brugada syndrome was described to be compound heterozygous for this mutation in conjunction with another SCN5A alteration on the opposite chromosome, and induced pluripotent stem cell-derived cardiomyocytes generated from this patient exhibited significantly reduced sodium current. The p.R1629* mutation co-segregated with disease from parent to child, and in vitro functional analyses indicated p.R1629* sodium channels have virtually no activity (Tan BY et al. Europace. 2015:1-8.doi:10.1093/europace/euv058; Ma D et al. Sci Rep. 2018;8:11246).Based on the available evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Mar 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Brugada syndrome 1
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001136449.2
First in ClinVar: Jan 09, 2020 Last updated: Mar 18, 2023 |
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Pathogenic
(Jul 20, 2023)
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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: SCV000515730.5
First in ClinVar: Mar 08, 2017 Last updated: Aug 13, 2023 |
Comment:
Identified in a patient with possible long QT syndrome in the published literature (Chae et al., 2017); Published functional studies demonstrate a damaging effect as … (more)
Identified in a patient with possible long QT syndrome in the published literature (Chae et al., 2017); Published functional studies demonstrate a damaging effect as the sodium current is abolished (Tan et al., 2015; Ma et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation, as the last 388 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 25829473, 30050137, 20129283, 30662450, 27871843, 30193851, 30203441, 34649698, 33131149) (less)
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Pathogenic
(Nov 10, 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: SCV000827405.3
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg1629*) in the SCN5A gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Arg1629*) in the SCN5A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 388 amino acid(s) of the SCN5A protein. This variant is present in population databases (rs199473284, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with Brugada syndrome (PMID: 20129283, 25829473). ClinVar contains an entry for this variant (Variation ID: 264276). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects SCN5A function (PMID: 25829473). This variant disrupts a region of the SCN5A protein in which other variant(s) (p.Glu1823Hisfs*10) have been determined to be pathogenic (PMID: 17897635, 18361072). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (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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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 I(Na)-dependent and I(to)-mediated proarrhythmic mechanism in cardiomyocytes derived from pluripotent stem cells of a Brugada syndrome patient. | Ma D | Scientific reports | 2018 | PMID: 30050137 |
A Brugada syndrome proband with compound heterozygote SCN5A mutations identified from a Chinese family in Singapore. | Tan BY | Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology | 2016 | PMID: 25829473 |
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 |
A novel SCN5A deletion mutation in a child with ventricular tachycardia, recurrent aborted sudden death, and Brugada electrocardiographic pattern. | Márquez MF | Archivos de cardiologia de Mexico | 2007 | PMID: 18361072 |
A novel C-terminal truncation SCN5A mutation from a patient with sick sinus syndrome, conduction disorder and ventricular tachycardia. | Tan BH | Cardiovascular research | 2007 | PMID: 17897635 |
Text-mined citations for rs199473284 ...
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.