ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.1890G>A (p.Thr630=)
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.
Pathogenic(1); Likely pathogenic(3); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000335.5(SCN5A):c.1890G>A (p.Thr630=)
Variation ID: 505275 Accession: VCV000505275.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 38603712 (GRCh38) [ NCBI UCSC ] 3: 38645203 (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 9, 2018 Aug 11, 2024 Apr 11, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000335.5:c.1890G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000326.2:p.Thr630= synonymous NM_001099404.2:c.1890G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001092874.1:p.Thr630= synonymous NM_001099405.2:c.1890G>A NP_001092875.1:p.Thr630= synonymous NM_001160160.2:c.1890G>A NP_001153632.1:p.Thr630= synonymous NM_001160161.2:c.1890G>A NP_001153633.1:p.Thr630= synonymous NM_001354701.2:c.1890G>A NP_001341630.1:p.Thr630= synonymous NM_198056.3:c.1890G>A NP_932173.1:p.Thr630= synonymous NC_000003.12:g.38603712C>T NC_000003.11:g.38645203C>T NG_008934.1:g.50961G>A LRG_289:g.50961G>A LRG_289t1:c.1890G>A LRG_289p1:p.Thr630= - Protein change
- Other names
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- Canonical SPDI
- NC_000003.12:38603711:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- 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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 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
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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 |
3779 | 4219 |
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
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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Uncertain significance (1) |
criteria provided, single submitter
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Sep 21, 2016 | RCV000602538.12 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 11, 2024 | RCV000618308.14 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 29, 2019 | RCV001841492.9 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 5, 2022 | RCV002298705.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 4, 2024 | RCV003541209.2 |
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. |
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Uncertain significance
(Sep 21, 2016)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000712425.2
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
Variant classified as Uncertain Significance - Favor Pathogenic. The p.Thr630Thr variant in SCN5A has been reported in 4 individuals with Brugada syndrome (Kapp linger 2010, … (more)
Variant classified as Uncertain Significance - Favor Pathogenic. The p.Thr630Thr variant in SCN5A has been reported in 4 individuals with Brugada syndrome (Kapp linger 2010, Chockalingam 2012) and was absent from large population studies. Th is variant is located in the last three bases of the exon, which is part of the 5? splice region. Computational predictions suggest a possible effect but functi onal assays would be needed to confirm this. Splice variants often lead to loss of function, which is an established mechanism for this gene for Brugada syndrom e. In summary, the absence from large populations, occurrence in several proband s with a consistent phenotype and location of the variant provide some support f or a role in disease; however, without additional evidence the clinical signific ance of the p.Thr630Thr variant remains uncertain. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Oct 29, 2019)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmia
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001361002.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: SCN5A c.1890G>A (p.Thr630Thr) alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a … (more)
Variant summary: SCN5A c.1890G>A (p.Thr630Thr) alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: One predicts that the variant abolishes a 5' splicing donor site, while four predict that the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 5.7e-06 in 174574 control chromosomes (gnomAD). c.1890G>A has been reported in the literature in individuals affected with Arrhythmia [e.g. Kapplinger_2010 (Brugada Syndrome), Chockalingham_2012, Baruteau_2018]. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions (evaluation after 2014) cites the variant once as likely pathogenic and once as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Likely pathogenic
(Oct 05, 2022)
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criteria provided, single submitter
Method: research, in vitro
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Brugada syndrome 1
Affected status: not applicable, unknown
Allele origin:
unknown,
not applicable
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Roden Lab, Vanderbilt University Medical Center
Accession: SCV002588734.1
First in ClinVar: Nov 05, 2022 Last updated: Nov 05, 2022 |
Comment:
The synonymous SCN5A variant c.1890G>A was observed in 1 case of Brugada Syndrome and is absent from large population databases (PMID: 32893267). The variant is … (more)
The synonymous SCN5A variant c.1890G>A was observed in 1 case of Brugada Syndrome and is absent from large population databases (PMID: 32893267). The variant is predicted to alter RNA splicing. A minigene functional assay showed aberrant splicing induced by the variant. These findings support the classification of this variant as Likely Pathogenic (less)
Observation 1: Observation 2:
Method: Minigene Assay
Result:
A HEK293T minigene assay showed pseudoexon inclusion and loss of canonical splicing in the variant but not WT plasmid.
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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: SCV001574354.3
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects codon 630 of the SCN5A mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid … (more)
This sequence change affects codon 630 of the SCN5A mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the SCN5A protein. This variant also falls at the last nucleotide of exon 12, which is part of the consensus splice site for this exon. This variant is present in population databases (no rsID available, gnomAD 0.005%). This variant has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 20129283, 22885917, 30193851, 33221895). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 505275). 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). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Apr 11, 2024)
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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: SCV000737544.7
First in ClinVar: Apr 14, 2018 Last updated: Aug 11, 2024 |
Comment:
The c.1890G>A (p.T630T) alteration is located in exon 12 (coding exon 11) of the SCN5A gene. This alteration consists of a G to A substitution … (more)
The c.1890G>A (p.T630T) alteration is located in exon 12 (coding exon 11) of the SCN5A gene. This alteration consists of a G to A substitution at nucleotide position 1890. This nucleotide substitution does not change the threonine at codon 630. However, this change occurs in the last base pair of coding exon 11, which makes it likely to have some effect on normal mRNA splicing. Based on data from gnomAD, the A allele has an overall frequency of 0.001% (1/174574) total alleles studied. The highest observed frequency was 0.005% (1/21048) of Latino alleles. This variant was observed in individuals reported to have Brugada syndrome; however, clinical details were limited (Kapplinger, 2010; Chockalingam, 2012). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as likely pathogenic. (less)
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Germline Functional Evidence
Functional
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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
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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. |
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sequence_variant_affecting_splicing
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Roden Lab, Vanderbilt University Medical Center
Accession: SCV002588734.1
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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 |
Brugada syndrome genetics is associated with phenotype severity. | Ciconte G | European heart journal | 2021 | PMID: 33221895 |
Impact of Ancestral Differences and Reassessment of the Classification of Previously Reported Pathogenic Variants in Patients With Brugada Syndrome in the Genomic Era: A SADS-TW BrS Registry. | Chen CJ | Frontiers in genetics | 2019 | PMID: 30662450 |
Clinical presentation and follow-up of women affected by Brugada syndrome. | Berthome P | Heart rhythm | 2019 | PMID: 30193851 |
SCN5A mutations in 442 neonates and children: genotype-phenotype correlation and identification of higher-risk subgroups. | Baruteau AE | European heart journal | 2018 | PMID: 30059973 |
The diagnostic and therapeutic aspects of loss-of-function cardiac sodium channelopathies in children. | Chockalingam P | Heart rhythm | 2012 | PMID: 22885917 |
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 |
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 |
Text-mined citations for rs1204915217 ...
HelpRecord last updated Oct 08, 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.