ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.611+1G>A
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.611+1G>A
Variation ID: 201427 Accession: VCV000201427.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 38620842 (GRCh38) [ NCBI UCSC ] 3: 38662333 (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 9, 2016 Sep 16, 2024 Mar 13, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000335.5:c.611+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001099404.2:c.611+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.611+1G>A splice donor NM_001160160.2:c.611+1G>A splice donor NM_001160161.2:c.611+1G>A splice donor NM_001354701.2:c.611+1G>A splice donor NM_001407185.1:c.611+1G>A splice donor NM_198056.3:c.611+1G>A splice donor NC_000003.12:g.38620842C>T NC_000003.11:g.38662333C>T NG_008934.1:g.33831G>A LRG_289:g.33831G>A LRG_289t1:c.611+1G>A - Protein change
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- Other names
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- Canonical SPDI
- NC_000003.12:38620841: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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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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The Genome Aggregation Database (gnomAD) 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00001
- Links
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 |
3783 | 4225 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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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Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 13, 2024 | RCV000182920.9 | |
Pathogenic (1) |
criteria provided, single submitter
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May 24, 2017 | RCV000519472.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 19, 2022 | RCV000619916.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 16, 2024 | RCV003591704.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 30, 2023 | RCV003996806.2 | |
SCN5A-related disorder
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not provided (1) |
no classification provided
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- | RCV004545756.1 |
Submissions - Germline
Classification
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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
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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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Pathogenic
(May 24, 2017)
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criteria provided, single submitter
Method: clinical testing
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Brugada syndrome 1
Affected status: yes
Allele origin:
unknown
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Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues
Accession: SCV000616617.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
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Pathogenic
(Jan 04, 2024)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000637200.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change affects a donor splice site in intron 5 of the SCN5A gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more)
This sequence change affects a donor splice site in intron 5 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Brugada syndrome (PMID: 20129283, 29709101). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 201427). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 19, 2022)
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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: SCV000737525.5
First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024 |
Comment:
The c.611+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 4 of the SCN5A gene. Alterations that disrupt … (more)
The c.611+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 4 of the SCN5A gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). This alteration has been described in individuals and families with Brugada syndrome; of note, at least one individual had a co-occurring SCN5A alteration also detected, and one reportedly unaffected carrier was also described (Kapplinger JD et al. Heart Rhythm, 2010 Jan;7:33-46; Robyns T et al. Ann Noninvasive Electrocardiol, 2018 09;23:e12548; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298) This variant has also been observed in a long QT syndrome cohort; however, clinical details were limited (Christiansen M et al. BMC Med Genet, 2014 Mar;15:31). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Mar 13, 2024)
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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: SCV000235315.14
First in ClinVar: Jul 05, 2015 Last updated: Sep 16, 2024 |
Comment:
Identified in patients with Long QT syndrome and Brugada syndrome referred for genetic testing at GeneDx and in published literature (PMID: 20129283, 24606995, 29709101, 30690642, … (more)
Identified in patients with Long QT syndrome and Brugada syndrome referred for genetic testing at GeneDx and in published literature (PMID: 20129283, 24606995, 29709101, 30690642, 31737537, 34461752); Not observed in large population cohorts (gnomAD); Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 20129283, 25525159, 31737537, 24606995, 29709101, 30690642, 34461752) (less)
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Pathogenic
(Jan 16, 2024)
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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: SCV004362239.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This variant (also known as IVS5+1G>A in published literature) causes a G to A nucleotide substitution at the +1 position of intron 5 of the … (more)
This variant (also known as IVS5+1G>A in published literature) causes a G to A nucleotide substitution at the +1 position of intron 5 of the SCN5A gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in about ten individuals affected with Brugada syndrome (PMID: 20129283, 29709101, 29884292, 32893267), in two young individuals affected with sinus node dysfunction (PMID: 26111534, 37746560), in an individual affected with mitral valve dilatation (PMID: 36143288), and in an individual affected with long QT syndrome (PMID 24606995). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of SCN5A function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Oct 30, 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: SCV004839345.1
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 disrupts a canonical splice site and is predicted to result in abnormal splicing. Aberrant splicing and/or loss of function is an established mechanism … (more)
This variant disrupts a canonical splice site and is predicted to result in abnormal splicing. Aberrant splicing and/or loss of function is an established mechanism of disease. This prediction has not been confirmed by functional studies. This variant has been reported in multiple individuals with Brugada syndrome and long QT syndrome (PMID: 20129283, 24606995, 29709101, 29884292, 32893267). This variant is absent from or rare in large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). (less)
Number of individuals with the variant: 1
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not provided
(-)
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no classification provided
Method: phenotyping only
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SCN5A-related conditions
Affected status: unknown
Allele origin:
unknown
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GenomeConnect - Invitae Patient Insights Network
Accession: SCV001749523.1
First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021 |
Comment:
Variant interpreted as Pathogenic and reported on 06-19-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report … (more)
Variant interpreted as Pathogenic and reported on 06-19-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Clinical Features:
Hypercholesterolemia (present)
Age: 50-59 years
Sex: male
Testing laboratory: Invitae
Date variant was reported to submitter: 2020-06-19
Testing laboratory interpretation: Pathogenic
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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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A novel association between sinus node dysfunction and an SCN5A variant presenting as persistent symptomatic bradycardia in a young adult. | Kisling A | HeartRhythm case reports | 2023 | PMID: 37746560 |
Landscape of Secondary Findings in Chinese Population: A Practice of ACMG SF v3.0 List. | Huang Y | Journal of personalized medicine | 2022 | PMID: 36143288 |
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 |
Role of genetic heart disease in sentinel sudden cardiac arrest survivors across the age spectrum. | Giudicessi JR | International journal of cardiology | 2018 | PMID: 29884292 |
Genotype-phenotype relationship and risk stratification in loss-of-function SCN5A mutation carriers. | Robyns T | Annals of noninvasive electrocardiology : the official journal of the International Society for Holter and Noninvasive Electrocardiology, Inc | 2018 | PMID: 29709101 |
Loss-of-Function SCN5A Mutations Associated With Sinus Node Dysfunction, Atrial Arrhythmias, and Poor Pacemaker Capture. | Chiang DY | Circulation. Arrhythmia and electrophysiology | 2015 | PMID: 26111534 |
Mutations in Danish patients with long QT syndrome and the identification of a large founder family with p.F29L in KCNH2. | Christiansen M | BMC medical genetics | 2014 | PMID: 24606995 |
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 |
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Text-mined citations for rs794728843 ...
HelpRecord 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.