Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease; Published functional studies demonstrate a damaging effect as the variant results in the use of a cryptic spice donor site downstream of the natural donor site, leading to a frameshift (O'Neill et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21273195, 33221895, 25525159, 19251209, 20129283, 21321465, 29709101, 29709244, 36197721, 35124229)
ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.4434+5G>A
Germline
Classification
Help
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.
(8)
Help
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.
Conflicting classifications of pathogenicity
Likely pathogenic(5); Uncertain significance(2)
Likely pathogenic(5); Uncertain significance(2)
8
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000335.5(SCN5A):c.4434+5G>A
Variation ID: 379225 Accession: VCV000379225.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 38556436 (GRCh38) [ NCBI UCSC ] 3: 38597927 (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 Apr 23, 2017 Nov 3, 2024 Mar 1, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000335.5:c.4434+5G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001099404.2:c.4437+5G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001099404.1:c.4437+5G>A NM_001099405.2:c.4383+5G>A intron variant NM_001160160.2:c.4434+5G>A intron variant NM_001160161.2:c.4275+5G>A intron variant NM_001354701.2:c.4380+5G>A intron variant NM_198056.3:c.4437+5G>A intron variant NC_000003.12:g.38556436C>T NC_000003.11:g.38597927C>T NG_008934.1:g.98237G>A LRG_289:g.98237G>A LRG_289t1:c.4437+5G>A - Protein change
- -
- Other names
- -
- Canonical SPDI
- NC_000003.12:38556435:C:T
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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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sequence_variant_affecting_splicing; Sequence Ontology [ SO:1000071]
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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.
- -
- Links
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 |
3793 | 4237 | |
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. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Jan 11, 2024 | RCV000429534.7 | |
| Uncertain significance (1) |
no assertion criteria provided
|
Aug 23, 2016 | RCV000477868.1 | |
| Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 5, 2022 | RCV001256847.3 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Jan 11, 2022 | RCV002328929.2 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Mar 1, 2024 | RCV004772906.2 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Jan 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000515906.5
First in ClinVar: Mar 08, 2017 Last updated: Apr 30, 2023 |
Comment:
Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease; Published functional studies demonstrate a damaging … (more)
Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease; Published functional studies demonstrate a damaging effect as the variant results in the use of a cryptic spice donor site downstream of the natural donor site, leading to a frameshift (O'Neill et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21273195, 33221895, 25525159, 19251209, 20129283, 21321465, 29709101, 29709244, 36197721, 35124229) (less)
|
|
|
Likely pathogenic
(Mar 11, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Brugada syndrome 1
Affected status: yes
Allele origin:
germline
|
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV001433332.1
First in ClinVar: Sep 27, 2020 Last updated: Sep 27, 2020 |
|
|
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Likely pathogenic
(Oct 05, 2022)
|
criteria provided, single submitter
Method: research, in vitro
|
Brugada syndrome 1
Affected status: unknown, not applicable
Allele origin:
unknown,
not applicable
|
Roden Lab, Vanderbilt University Medical Center
Accession: SCV002588735.1
First in ClinVar: Nov 05, 2022 Last updated: Nov 05, 2022 |
Comment:
The SCN5A variant c.4437+5G>A was observed in 2 cases of Brugada Syndrome and is absent from large population databases (PMID: 32893267). The variant is predicted … (more)
The SCN5A variant c.4437+5G>A was observed in 2 cases of Brugada Syndrome and is absent from large population databases (PMID: 32893267). The variant is predicted to alter mRNA splicing. Functional investigations in an iPSC-CM model showed pseudoexon inclusion induced by the edited allele that introduced a frameshift in the predominant aberrantly spliced product. These findings collectively support a Likely Pathogenic classification. (less)
Observation 1: Observation 2:
Method: Transcriptional analysis of CRISPR-Cas9 edited iPSC-CMs.
Result:
Introduction of the variant as a heterozygous edit by CRISPR-Cas9 in a healthy control induced pluripotent stem cell line was observed to cause pseudoexon inclusion of the edited allele, provoking a frameshift.
|
|
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Likely pathogenic
(Jan 11, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001382063.4
First in ClinVar: Jul 16, 2020 Last updated: Feb 28, 2024 |
Comment:
This sequence change falls in intron 25 of the SCN5A gene. It does not directly change the encoded amino acid sequence of the SCN5A protein. … (more)
This sequence change falls in intron 25 of the SCN5A gene. It does not directly change the encoded amino acid sequence of the SCN5A protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of SCN5A-related conditions (PMID: 19251209, 21321465, 33221895, 35124229, 36578016; Invitae). ClinVar contains an entry for this variant (Variation ID: 379225). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 36197721). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
|
|
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Uncertain significance
(Jan 11, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002631295.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.4437+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 24 in the SCN5A gene. This variant has been … (more)
The c.4437+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 24 in the SCN5A gene. This variant has been seen in several Brugada syndrome (BrS) cohorts (Ciconte G et al. Eur Heart J, 2021 03;42:1082-1090; Amin AS et al. Int J Cardiol, 2018 Sep;266:128-132; Nakajima T et al. Int Heart J, 2011;52:27-31; Meregalli PG et al. Heart Rhythm, 2009 Mar;6:341-8). This nucleotide position is highly conserved in available vertebrate species. This alteration is located within a U12-type intron and in silico tools are not reliable predictors of splice sites in this type of intron. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
|
|
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Likely pathogenic
(Mar 01, 2024)
|
criteria provided, single submitter
Method: research
|
Atrial fibrillation
Affected status: yes
Allele origin:
germline
|
Lildballe Lab, Aarhus University Hospital
Accession: SCV005200566.1
First in ClinVar: Nov 03, 2024 Last updated: Nov 03, 2024 |
Comment:
PS4(s) PM2(s) PP3(sup) PP5(noinf)
|
|
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Uncertain significance
(May 27, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005196826.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
|
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Uncertain significance
(Aug 23, 2016)
|
no assertion criteria provided
Method: research
|
Long QT syndrome 3
Affected status: yes
Allele origin:
maternal
|
Division of Human Genetics, Children's Hospital of Philadelphia
Study: CSER-PediSeq
Accession: SCV000536910.1 First in ClinVar: Apr 23, 2017 Last updated: Apr 23, 2017 |
|
Comment:
Comment:
The SCN5A variant c.4437+5G>A was observed in 2 cases of Brugada Syndrome and is absent from large population databases (PMID: 32893267). The variant is predicted to alter mRNA splicing. Functional investigations in an iPSC-CM model showed pseudoexon inclusion induced by the edited allele that introduced a frameshift in the predominant aberrantly spliced product. These findings collectively support a Likely Pathogenic classification.
Comment:
This sequence change falls in intron 25 of the SCN5A gene. It does not directly change the encoded amino acid sequence of the SCN5A protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of SCN5A-related conditions (PMID: 19251209, 21321465, 33221895, 35124229, 36578016; Invitae). ClinVar contains an entry for this variant (Variation ID: 379225). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 36197721). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Comment:
The c.4437+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 24 in the SCN5A gene. This variant has been seen in several Brugada syndrome (BrS) cohorts (Ciconte G et al. Eur Heart J, 2021 03;42:1082-1090; Amin AS et al. Int J Cardiol, 2018 Sep;266:128-132; Nakajima T et al. Int Heart J, 2011;52:27-31; Meregalli PG et al. Heart Rhythm, 2009 Mar;6:341-8). This nucleotide position is highly conserved in available vertebrate species. This alteration is located within a U12-type intron and in silico tools are not reliable predictors of splice sites in this type of intron. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
PS4(s) PM2(s) PP3(sup) PP5(noinf)
Germline Functional Evidence
| Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|---|---|---|---|
|
sequence_variant_affecting_splicing
|
|
|
Roden Lab, Vanderbilt University Medical Center
Accession: SCV002588735.1
|
|
Comment:
Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease; Published functional studies demonstrate a damaging effect as the variant results in the use of a cryptic spice donor site downstream of the natural donor site, leading to a frameshift (O'Neill et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21273195, 33221895, 25525159, 19251209, 20129283, 21321465, 29709101, 29709244, 36197721, 35124229)
Comment:
The SCN5A variant c.4437+5G>A was observed in 2 cases of Brugada Syndrome and is absent from large population databases (PMID: 32893267). The variant is predicted to alter mRNA splicing. Functional investigations in an iPSC-CM model showed pseudoexon inclusion induced by the edited allele that introduced a frameshift in the predominant aberrantly spliced product. These findings collectively support a Likely Pathogenic classification.
Comment:
This sequence change falls in intron 25 of the SCN5A gene. It does not directly change the encoded amino acid sequence of the SCN5A protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of SCN5A-related conditions (PMID: 19251209, 21321465, 33221895, 35124229, 36578016; Invitae). ClinVar contains an entry for this variant (Variation ID: 379225). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 36197721). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Comment:
The c.4437+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 24 in the SCN5A gene. This variant has been seen in several Brugada syndrome (BrS) cohorts (Ciconte G et al. Eur Heart J, 2021 03;42:1082-1090; Amin AS et al. Int J Cardiol, 2018 Sep;266:128-132; Nakajima T et al. Int Heart J, 2011;52:27-31; Meregalli PG et al. Heart Rhythm, 2009 Mar;6:341-8). This nucleotide position is highly conserved in available vertebrate species. This alteration is located within a U12-type intron and in silico tools are not reliable predictors of splice sites in this type of intron. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
PS4(s) PM2(s) PP3(sup) PP5(noinf)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Automated variant re-evaluation is labor-balanced and gives clinically relevant results: Hereditary cardiac disease as a use case. | Grosen A | European journal of medical genetics | 2024 | PMID: 39481677 |
| The role of genetic testing in diagnosis and care of inherited cardiac conditions in a specialised multidisciplinary clinic. | Stafford F | Genome medicine | 2022 | PMID: 36578016 |
| 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 |
| Brugada syndrome genetics is associated with phenotype severity. | Ciconte G | European heart journal | 2021 | PMID: 33221895 |
| SCN5A mutation type and topology are associated with the risk of ventricular arrhythmia by sodium channel blockers. | Amin AS | International journal of cardiology | 2018 | PMID: 29709244 |
| The role of metabolomics in osteoarthritis for early diagnosis, monitoring prognosis and treatment. | Atik OŞ | Eklem hastaliklari ve cerrahisi = Joint diseases & related surgery | 2015 | PMID: 25741911 |
| Identification of six novel SCN5A mutations in Japanese patients with Brugada syndrome. | Nakajima T | International heart journal | 2011 | PMID: 21321465 |
| 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 |
| Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
| Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
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Text-mined citations for rs1057520531 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 25, 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.