ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.3142_3153delinsTCTGACTGTGT (p.Pro1048fs)
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.3142_3153delinsTCTGACTGTGT (p.Pro1048fs)
Variation ID: 201564 Accession: VCV000201564.8
- Type and length
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Indel, 12 bp
- Location
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Cytogenetic: 3p22.2 3: 38581006-38581017 (GRCh38) [ NCBI UCSC ] 3: 38622497-38622508 (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 Mar 8, 2017 Mar 16, 2024 Nov 18, 2023 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- P1048fs
- Other names
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- Canonical SPDI
- NC_000003.12:38581005:CACAGCGATGGG:ACACAGTCAGA
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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
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 |
3724 | 4156 | |
LOC110121269 | - | - | - | GRCh38 | - | 413 |
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
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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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Sep 8, 2021 | RCV000183158.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 9, 2021 | RCV002321726.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 18, 2023 | RCV003977487.1 |
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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Pathogenic
(Jul 09, 2021)
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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: SCV002609037.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The c.3142_3153del12ins11 pathogenic mutation, located in coding exon 16 of the SCN5A gene, results from the deletion of 12 nucleotides and insertion of 11 nucleotides … (more)
The c.3142_3153del12ins11 pathogenic mutation, located in coding exon 16 of the SCN5A gene, results from the deletion of 12 nucleotides and insertion of 11 nucleotides causing a translational frameshift with a predicted alternate stop codon (p.P1048Sfs*97), and is located in the interdomain linker DII/DIII region. This variant was reported in a child with syncope, progressive sinus node dysfunction, and His-Purkinje system disease with atrial standstill, who also had an SCN5A missense variant detected in trans; her mother and sister, who were heterozygous for only c.3142_3153del12ins11, showed mild cardiac findings but were asymptomatic at the time of evaluation (Baskar S et al. J Pediatr, 2014 Nov;165:1050-2). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Sep 03, 2019)
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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: SCV000235574.13
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
Frameshift variant predicted to result in protein truncation [or nonsense mediated decay] in a gene for which loss-of-function is a known mechanism of disease; Not … (more)
Frameshift variant predicted to result in protein truncation [or nonsense mediated decay] in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25171853) (less)
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Pathogenic
(Sep 08, 2021)
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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: SCV004673466.1
First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, … (more)
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This premature translational stop signal has been observed in individual(s) with clinical features of SCN5A-related disease (PMID: 25171853). The frequency data for this variant in the population databases is not available, as this variant may be reported as separate entries in the ExAC database. This sequence change creates a premature translational stop signal (p.Pro1048Serfs*97) in the SCN5A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SCN5A are known to be pathogenic (PMID: 20129283, 22789973). (less)
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Pathogenic
(Nov 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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SCN5A-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004790150.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The SCN5A c.3142_3153delinsTCTGACTGTGT variant is predicted to result in a frameshift and premature protein termination (p.Pro1048Serfs*97). This variant was reported in the compound heterozygous state … (more)
The SCN5A c.3142_3153delinsTCTGACTGTGT variant is predicted to result in a frameshift and premature protein termination (p.Pro1048Serfs*97). This variant was reported in the compound heterozygous state in an individual with atrial standstill and His-Purkinje system disease. This variant was also identified in this individual's mother and sister who did not carry the other SCN5A variant and had milder phenotypic manifestations (Baskar et al. 2014. PubMed ID: 25171853). In the same publication, this variant was also reported in an unrelated individual with Brugada syndrome, although detailed clinical information was not available. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in SCN5A are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
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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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Compound heterozygous mutations in the SCN5A-encoded Nav1.5 cardiac sodium channel resulting in atrial standstill and His-Purkinje system disease. | Baskar S | The Journal of pediatrics | 2014 | PMID: 25171853 |
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 |
Text-mined citations for rs794728917 ...
HelpRecord last updated Apr 20, 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.