ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.5353_5354del (p.Leu1785fs)
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.5353_5354del (p.Leu1785fs)
Variation ID: 254156 Accession: VCV000254156.11
- Type and length
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Deletion, 2 bp
- Location
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Cytogenetic: 3p22.2 3: 38551015-38551016 (GRCh38) [ NCBI UCSC ] 3: 38592506-38592507 (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 Sep 10, 2016 Apr 20, 2024 Dec 15, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000335.5:c.5353_5354del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000326.2:p.Leu1785fs frameshift NM_001099404.2:c.5356_5357del MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001092874.1:p.Leu1786fs frameshift NM_001099405.2:c.5302_5303del NP_001092875.1:p.Leu1768fs frameshift NM_001160160.2:c.5257_5258del NP_001153632.1:p.Leu1753fs frameshift NM_001160161.2:c.5194_5195del NP_001153633.1:p.Leu1732fs frameshift NM_001354701.2:c.5299_5300del NP_001341630.1:p.Leu1767fs frameshift NM_198056.2:c.5356_5357delCT NM_198056.3:c.5356_5357del NP_932173.1:p.Leu1786fs frameshift NC_000003.12:g.38551015_38551016del NC_000003.11:g.38592506_38592507del NG_008934.1:g.103657_103658del LRG_289:g.103657_103658del LRG_289t1:c.5356_5357del LRG_289p1:p.Leu1786fs - Protein change
- L1732fs, L1768fs, L1785fs, L1767fs, L1753fs, L1786fs
- Other names
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- Canonical SPDI
- NC_000003.12:38551014:AG:
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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
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
3773 | 4212 |
Conditions - Germline
Condition
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Jan 1, 2016 | RCV000240623.9 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 6, 2023 | RCV003226916.9 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Dec 15, 2023 | RCV003998945.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Dec 2, 2019 | RCV001843012.10 |
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
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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
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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
(Jan 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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Brugada syndrome 1
Affected status: yes
Allele origin:
germline
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Center for Medical Genetics Ghent, University of Ghent
Accession: SCV000299254.2
First in ClinVar: Sep 10, 2016 Last updated: Sep 10, 2016 |
Comment:
This variant has not been identified in large population databases (Gnomad, 1000 Genomes, Go NL, Exome Variant Server) and is predicted to cause loss of … (more)
This variant has not been identified in large population databases (Gnomad, 1000 Genomes, Go NL, Exome Variant Server) and is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. (less)
Sex: male
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Likely pathogenic
(Dec 02, 2019)
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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: SCV001343337.2
First in ClinVar: Jun 22, 2020 Last updated: Jan 12, 2022 |
Comment:
This variant deletes 2 nucleotides in exon 28 of the SCN5A gene, creating a frameshift and premature translation stop signal in the last exon. This … (more)
This variant deletes 2 nucleotides in exon 28 of the SCN5A gene, creating a frameshift and premature translation stop signal in the last exon. This variant is expected to result in a truncated protein product. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Truncation variants occurring C-terminal to this variant have been reported in individuals affected with long QT syndrome (Clinvar). 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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Likely pathogenic
(Nov 01, 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: SCV003923875.1
First in ClinVar: May 13, 2023 Last updated: May 13, 2023 |
Comment:
Reported as a maternally-inherited variant in a child who presented with atrial flutter and ventricular tachycardia without structural heart disease; the mother also demonstrated atrial … (more)
Reported as a maternally-inherited variant in a child who presented with atrial flutter and ventricular tachycardia without structural heart disease; the mother also demonstrated atrial flutter and sick sinus syndrome (Abe et al., 2014); Frameshift variant predicted to result in protein truncation, as the last 231 amino acids are replaced with 1 different amino acid, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24762805, 33131149, 29728395, 16643399, 33164571, 20129283, 30662450, 28781330, 30193851) (less)
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Pathogenic
(Nov 06, 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: SCV003525422.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Leu1786Glufs*2) 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.Leu1786Glufs*2) in the SCN5A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 231 amino acid(s) of the SCN5A protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with a personal and/or family history of Brugada syndrome (PMID: 20129283, 24762805, 30193851). ClinVar contains an entry for this variant (Variation ID: 254156). This variant disrupts a region of the SCN5A protein in which other variant(s) (p.Glu1867*) have been determined to be pathogenic (PMID: 16267250, 19406494, 24895455; 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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Likely Pathogenic
(Dec 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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Brugada syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004843392.1
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)
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Comment:
This variant deletes 2 nucleotides in exon 28 of the SCN5A gene, creating a frameshift and premature translation stop signal in the last exon. This … (more)
This variant deletes 2 nucleotides in exon 28 of the SCN5A gene, creating a frameshift and premature translation stop signal in the last exon. This variant is expected to result in a truncated protein product. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Truncation variants occurring C-terminal to this variant have been reported in individuals affected with long QT syndrome (Clinvar). Loss of SCN5A function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
Number of individuals with the variant: 1
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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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Clinical presentation and follow-up of women affected by Brugada syndrome. | Berthome P | Heart rhythm | 2019 | PMID: 30193851 |
PDZ domain-binding motif regulates cardiomyocyte compartment-specific NaV1.5 channel expression and function. | Shy D | Circulation | 2014 | PMID: 24895455 |
Sodium channelopathy underlying familial sick sinus syndrome with early onset and predominantly male characteristics. | Abe K | Circulation. Arrhythmia and electrophysiology | 2014 | PMID: 24762805 |
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 |
Novel sodium channel SCN5A mutations in Brugada syndrome patients from Greece. | Kotta CM | International journal of cardiology | 2010 | PMID: 19406494 |
Right ventricular fibrosis and conduction delay in a patient with clinical signs of Brugada syndrome: a combined electrophysiological, genetic, histopathologic, and computational study. | Coronel R | Circulation | 2005 | PMID: 16267250 |
Text-mined citations for rs886037903 ...
HelpRecord last updated Sep 17, 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.