This variant affects the canonical splice donor site of intron 9 and is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous change in a patient with a diagnosis of Brugada syndrome. RT-PCR performed on lymphocytes obtained from the patient showed reduced levels of wild-type transcript, and in vitro transfection experiments demonstrated two aberrant transcripts that were predicted to undergo NMD (PMID: 24915601). Loss-of-function variation in SCN5A is an established mechanism of disease (PMID: 20129283, 29798782). The c.1140+1G>A variant is absent from the gnomAD population database and thus presumed to be rare. Based on the available evidence, the c.1140+1G>A variant is classified as Likely Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.1140+1G>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.
(5)
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.
Pathogenic/Likely pathogenic
5
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000335.5(SCN5A):c.1140+1G>A
Variation ID: 180520 Accession: VCV000180520.7
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 38648159 (GRCh37) [ NCBI UCSC ] 3: 38606668 (GRCh38) [ 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 Feb 7, 2015 Sep 1, 2024 Dec 15, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000335.5:c.1140+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001099404.2:c.1140+1G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001099405.2:c.1140+1G>A splice donor NM_001160160.2:c.1140+1G>A splice donor NM_001160161.2:c.1140+1G>A splice donor NM_001354701.2:c.1140+1G>A splice donor NM_001407185.1:c.1140+1G>A splice donor NM_198056.3:c.1140+1G>A splice donor NC_000003.12:g.38606668C>T NC_000003.11:g.38648159C>T NG_008934.1:g.48005G>A LRG_289:g.48005G>A LRG_289t3:c.1140+1G>A - Protein change
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- Other names
- -
- Canonical SPDI
- NC_000003.12:38606667: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]Perturbed RNA splicing [submitted by Roden Lab, Vanderbilt University Medical Center]
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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.
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- 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 |
3783 | 4225 | |
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. |
|---|---|---|---|---|
| Uncertain significance (1) |
no assertion criteria provided
|
Jul 18, 2014 | RCV000157497.1 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 15, 2023 | RCV003492635.1 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 26, 2022 | RCV003658426.2 | |
|
SCN5A-related disorder
|
Likely pathogenic (1) |
criteria provided, single submitter
|
- | RCV004545750.1 |
| Likely pathogenic (1) |
criteria provided, single submitter
|
- | RCV004698474.1 |
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
(-)
|
criteria provided, single submitter
Method: clinical testing
|
SCN5A-Related Disorders
Affected status: yes
Allele origin:
germline
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV004046183.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
This variant affects the canonical splice donor site of intron 9 and is predicted to result in loss of normal protein function through either protein … (more)
This variant affects the canonical splice donor site of intron 9 and is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous change in a patient with a diagnosis of Brugada syndrome. RT-PCR performed on lymphocytes obtained from the patient showed reduced levels of wild-type transcript, and in vitro transfection experiments demonstrated two aberrant transcripts that were predicted to undergo NMD (PMID: 24915601). Loss-of-function variation in SCN5A is an established mechanism of disease (PMID: 20129283, 29798782). The c.1140+1G>A variant is absent from the gnomAD population database and thus presumed to be rare. Based on the available evidence, the c.1140+1G>A variant is classified as Likely Pathogenic. (less)
|
|
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Pathogenic
(Dec 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Brugada syndrome (shorter-than-normal QT interval)
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004241183.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
Comment:
Variant summary: SCN5A c.1140+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to … (more)
Variant summary: SCN5A c.1140+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Di Resta_2014). The variant was absent in 247252 control chromosomes (gnomAD). c.1140+1G>A has been reported in the literature in an individual affected with Brugada Syndrome (Di Resta_2014). The following publication has been ascertained in the context of this evaluation (PMID: 24915601). One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
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Pathogenic
(Sep 26, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003269981.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 180520). For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption … (more)
ClinVar contains an entry for this variant (Variation ID: 180520). For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 24915601). Disruption of this splice site has been observed in individual(s) with asymptomatic Brugada syndrome (PMID: 24915601). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 9 of the SCN5A gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SCN5A are known to be pathogenic (PMID: 20129283, 22789973). (less)
|
|
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Likely pathogenic
(-)
|
criteria provided, single submitter
Method: research, in vitro
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Brugada syndrome 1
Affected status: not applicable, unknown
Allele origin:
germline,
not applicable
|
Roden Lab, Vanderbilt University Medical Center
Accession: SCV005200439.1
First in ClinVar: Sep 01, 2024 Last updated: Sep 01, 2024
Comment:
We classified this variant using data from the calibrated functional assay 'ParSE-seq' (PMID: 37732247), population data, and in silico data within the ACMG v3 framework … (more)
We classified this variant using data from the calibrated functional assay 'ParSE-seq' (PMID: 37732247), population data, and in silico data within the ACMG v3 framework (PMID: 25741868)The SCN5A variant, 3-38606668-C-T was evaluated for association with the loss-of-function condition Brugada Syndrome.This Variant had an AF of 0 in gnomAD v3The in silico predictor SpliceAI scored the variant as 0.991189; normal <0.2, likely damaging >0.5.Using the functional RNA-splicing assay, ParSE-seq, the variant was evaluated to have a strong negative impact on splicing (PS3_strong) following the Brnich et al. calibration framework (PMID: 31892348). In aggregate, we therefore classify this variant as LP using these collective data. (less)
|
Comment:
We classified this variant using data from the calibrated functional assay 'ParSE-seq' (PMID: 37732247), population data, and in silico data within the ACMG v3 framework … (more)
We classified this variant using data from the calibrated functional assay 'ParSE-seq' (PMID: 37732247), population data, and in silico data within the ACMG v3 framework (PMID: 25741868)The SCN5A variant, 3-38606668-C-T was evaluated for association with the loss-of-function condition Brugada Syndrome.This Variant had an AF of 0 in gnomAD v3The in silico predictor SpliceAI scored the variant as 0.991189; normal <0.2, likely damaging >0.5.Using the functional RNA-splicing assay, ParSE-seq, the variant was evaluated to have a strong negative impact on splicing (PS3_strong) following the Brnich et al. calibration framework (PMID: 31892348). In aggregate, we therefore classify this variant as LP using these collective data. (less)
Observation 1: Observation 2:
Comment on evidence:
Functional evidence assertions with RNA-splicing scores. Benign RNA-splicing scores were not applied to missense variants.
Method: Calibrated RNA splicing assay, ParSE-seq. Outcomes derived from OddsPath quantification on control variants.
Result:
Perturbed RNA splicing
|
|
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Uncertain significance
(Jul 18, 2014)
|
no assertion criteria provided
Method: clinical testing
|
Primary familial hypertrophic cardiomyopathy
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV000207242.1
First in ClinVar: Feb 07, 2015 Last updated: Feb 07, 2015 |
Number of individuals with the variant: 1
|
Comment:
Comment:
Variant summary: SCN5A c.1140+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Di Resta_2014). The variant was absent in 247252 control chromosomes (gnomAD). c.1140+1G>A has been reported in the literature in an individual affected with Brugada Syndrome (Di Resta_2014). The following publication has been ascertained in the context of this evaluation (PMID: 24915601). One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
ClinVar contains an entry for this variant (Variation ID: 180520). For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 24915601). Disruption of this splice site has been observed in individual(s) with asymptomatic Brugada syndrome (PMID: 24915601). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 9 of the SCN5A gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SCN5A are known to be pathogenic (PMID: 20129283, 22789973).
Comment:
We classified this variant using data from the calibrated functional assay 'ParSE-seq' (PMID: 37732247), population data, and in silico data within the ACMG v3 framework (PMID: 25741868)The SCN5A variant, 3-38606668-C-T was evaluated for association with the loss-of-function condition Brugada Syndrome.This Variant had an AF of 0 in gnomAD v3The in silico predictor SpliceAI scored the variant as 0.991189; normal <0.2, likely damaging >0.5.Using the functional RNA-splicing assay, ParSE-seq, the variant was evaluated to have a strong negative impact on splicing (PS3_strong) following the Brnich et al. calibration framework (PMID: 31892348). In aggregate, we therefore classify this variant as LP using these collective data.
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
|
Method citation(s):
|
|
Roden Lab, Vanderbilt University Medical Center
Accession: SCV005200439.1
|
Comment:
Perturbed RNA splicing
|
Comment:
This variant affects the canonical splice donor site of intron 9 and is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous change in a patient with a diagnosis of Brugada syndrome. RT-PCR performed on lymphocytes obtained from the patient showed reduced levels of wild-type transcript, and in vitro transfection experiments demonstrated two aberrant transcripts that were predicted to undergo NMD (PMID: 24915601). Loss-of-function variation in SCN5A is an established mechanism of disease (PMID: 20129283, 29798782). The c.1140+1G>A variant is absent from the gnomAD population database and thus presumed to be rare. Based on the available evidence, the c.1140+1G>A variant is classified as Likely Pathogenic.
Comment:
Variant summary: SCN5A c.1140+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Di Resta_2014). The variant was absent in 247252 control chromosomes (gnomAD). c.1140+1G>A has been reported in the literature in an individual affected with Brugada Syndrome (Di Resta_2014). The following publication has been ascertained in the context of this evaluation (PMID: 24915601). One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
ClinVar contains an entry for this variant (Variation ID: 180520). For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 24915601). Disruption of this splice site has been observed in individual(s) with asymptomatic Brugada syndrome (PMID: 24915601). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 9 of the SCN5A gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SCN5A are known to be pathogenic (PMID: 20129283, 22789973).
Comment:
We classified this variant using data from the calibrated functional assay 'ParSE-seq' (PMID: 37732247), population data, and in silico data within the ACMG v3 framework (PMID: 25741868)The SCN5A variant, 3-38606668-C-T was evaluated for association with the loss-of-function condition Brugada Syndrome.This Variant had an AF of 0 in gnomAD v3The in silico predictor SpliceAI scored the variant as 0.991189; normal <0.2, likely damaging >0.5.Using the functional RNA-splicing assay, ParSE-seq, the variant was evaluated to have a strong negative impact on splicing (PS3_strong) following the Brnich et al. calibration framework (PMID: 31892348). In aggregate, we therefore classify this variant as LP using these collective data.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| ParSE-seq: A Calibrated Multiplexed Assay to Facilitate the Clinical Classification of Putative Splice-altering Variants. | O'Neill MJ | medRxiv : the preprint server for health sciences | 2023 | PMID: 37732247 |
| Evaluation of damaging effects of splicing mutations: validation of an in vitro method for diagnostic laboratories. | Di Resta C | Clinica chimica acta; international journal of clinical chemistry | 2014 | PMID: 24915601 |
| Brugada syndrome 2012. | Berne P | Circulation journal : official journal of the Japanese Circulation Society | 2012 | PMID: 22789973 |
| 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 |
| Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
Text-mined citations for rs730880210 ...
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 10, 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.