ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.4716C>T (p.Gly1572=)
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.4716C>T (p.Gly1572=)
Variation ID: 263423 Accession: VCV000263423.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 38554373 (GRCh38) [ NCBI UCSC ] 3: 38595864 (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 20, 2024 Sep 8, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000335.5:c.4716C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000326.2:p.Gly1572= synonymous NM_001099404.2:c.4719C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001092874.1:p.Gly1573= synonymous NM_001099405.2:c.4665C>T NP_001092875.1:p.Gly1555= synonymous NM_001160160.2:c.4714+2C>T splice donor NM_001160161.2:c.4557C>T NP_001153633.1:p.Gly1519= synonymous NM_001354701.2:c.4662C>T NP_001341630.1:p.Gly1554= synonymous NM_198056.3:c.4719C>T NP_932173.1:p.Gly1573= synonymous NR_176299.1:n.5465C>T non-coding transcript variant NC_000003.12:g.38554373G>A NC_000003.11:g.38595864G>A NG_008934.1:g.100300C>T LRG_289:g.100300C>T LRG_289t1:c.4719C>T LRG_289p1:p.Gly1573= LRG_289t2:c.4716C>T LRG_289p2:p.Gly1572= LRG_289t3:c.4719C>T LRG_289p3:p.Gly1573= - Protein change
- Other names
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- Canonical SPDI
- NC_000003.12:38554372: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
Help
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), exomes 0.00001
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
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. |
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SCN5A | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3557 | 3958 |
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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Likely pathogenic (1) |
criteria provided, single submitter
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Nov 2, 2012 | RCV000253171.9 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jul 8, 2022 | RCV000498820.13 | |
Likely pathogenic (2) |
criteria provided, single submitter
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Sep 8, 2023 | RCV001843024.10 |
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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Likely pathogenic
(Nov 02, 2012)
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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: SCV000317855.5
First in ClinVar: Oct 03, 2016 Last updated: Oct 03, 2016 |
Number of individuals with the variant: 1
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Pathogenic
(Jul 08, 2022)
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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: SCV000589382.5
First in ClinVar: Aug 20, 2017 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect on sodium channel function (Bardai et al., 2013); In silico analysis supports a deleterious effect on splicing; Not … (more)
Published functional studies demonstrate a damaging effect on sodium channel function (Bardai et al., 2013); In silico analysis supports a deleterious effect on splicing; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31737537, 25525159, 23425522, 27668095, 25399282, 29759522, 30662450, 29709244, 35124229, 19843921) (less)
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Likely pathogenic
(Sep 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiac arrhythmia
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV004361621.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This synonymous variant causes a C>T nucleotide change in exon 27 of the SCN5A gene. This variant is also known as c.4716C>T based on a … (more)
This synonymous variant causes a C>T nucleotide change in exon 27 of the SCN5A gene. This variant is also known as c.4716C>T based on a different transcript NM_000335. Splice site prediction tools indicate that this variant may activate a cryptic splice donor site 96 nucleotides upstream of the native intron 27 splice donor site. Minigene assays and RNA studies with lymphocytes from a carrier have shown that this cryptic donor site is used and normal splicing is completely abolished, resulting in an in-frame deletion of 32 amino acids in the transmembrane domain DIV (PMID: 23425522, 36197721). Another functional study has shown that this variant causes a complete loss of sodium channel currents (PMID: 23425522). This variant has been reported in four individuals from three families affected with Brugada syndrome (PMID: 19843921, 23425522, 32893267, 35124229), in two related individuals affected with cardiac conduction disturbances (PMID: 27668095), and in another individual affected with bundle branch reentrant ventricular tachycardia (PMID: 29759522). This variant has been identified in 2/249326 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of SCN5A function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
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Pathogenic
(Jan 12, 2022)
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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: SCV001201210.4
First in ClinVar: Apr 15, 2020 Last updated: Feb 20, 2024 |
Comment:
Studies have shown that this variant results in the activation of a cryptic splice site in exon 27 (PMID: 23425522). ClinVar contains an entry for … (more)
Studies have shown that this variant results in the activation of a cryptic splice site in exon 27 (PMID: 23425522). ClinVar contains an entry for this variant (Variation ID: 263423). This variant has been observed in individual(s) with SCN5A-related conditions (PMID: 19843921, 27668095, 29759522, 31737537). This variant is present in population databases (rs754221948, gnomAD 0.003%). This sequence change affects codon 1573 of the SCN5A mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the SCN5A protein. RNA analysis indicates that this variant induces altered splicing and likely results in the loss of 32 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant disrupts a region of the SCN5A protein in which other variant(s) (p.Asp1595His) have been determined to be pathogenic (PMID: 15671429; Invitae). 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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Uncertain significance
(Aug 18, 2016)
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no assertion criteria provided
Method: clinical testing
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Cardiac arrhythmia
Affected status: yes
Allele origin:
germline
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Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital
Accession: SCV000805035.1
First in ClinVar: Sep 14, 2018 Last updated: Sep 14, 2018 |
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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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Functional Assays Reclassify Suspected Splice-Altering Variants of Uncertain Significance in Mendelian Channelopathies. | O'Neill MJ | Circulation. Genomic and precision medicine | 2022 | PMID: 36197721 |
SCN5A mutation in Brugada syndrome is associated with substrate severity detected by electrocardiographic imaging and high-density electroanatomic mapping. | Pannone L | Heart rhythm | 2022 | PMID: 35124229 |
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 |
Variant panorama in 1,385 index patients and sensitivity of expanded next-generation sequencing panels in arrhythmogenic disorders. | Marschall C | Cardiovascular diagnosis and therapy | 2019 | PMID: 31737537 |
Bundle Branch Re-Entrant Ventricular Tachycardia: Novel Genetic Mechanisms in a Life-Threatening Arrhythmia. | Roberts JD | JACC. Clinical electrophysiology | 2017 | PMID: 29759522 |
Epidural Analgesia with Ropivacaine during Labour in a Patient with a SCN5A Gene Mutation. | van der Knijff-van Dortmont AL | Case reports in anesthesiology | 2016 | PMID: 27668095 |
Sudden cardiac arrest associated with use of a non-cardiac drug that reduces cardiac excitability: evidence from bench, bedside, and community. | Bardai A | European heart journal | 2013 | PMID: 23425522 |
Exercise-induced ECG changes in Brugada syndrome. | Amin AS | Circulation. Arrhythmia and electrophysiology | 2009 | PMID: 19843921 |
Sodium channel mutations and susceptibility to heart failure and atrial fibrillation. | Olson TM | JAMA | 2005 | PMID: 15671429 |
Text-mined citations for rs754221948 ...
HelpRecord last updated Apr 15, 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.