ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.4471AAG[1] (p.Lys1492del)
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.4471AAG[1] (p.Lys1492del)
Variation ID: 222814 Accession: VCV000222814.5
- Type and length
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Microsatellite, 3 bp
- Location
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Cytogenetic: 3p22.2 3: 38555719-38555721 (GRCh38) [ NCBI UCSC ] 3: 38597210-38597212 (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 1, 2016 Feb 14, 2024 Dec 29, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000335.5:c.4471AAG[1] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000326.2:p.Lys1492del inframe deletion NM_001099404.2:c.4474AAG[1] MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001092874.1:p.Lys1493del inframe deletion NM_001099405.2:c.4420AAG[1] NP_001092875.1:p.Lys1475del inframe deletion NM_001160160.2:c.4471AAG[1] NP_001153632.1:p.Lys1492del inframe deletion NM_001160161.2:c.4312AAG[1] NP_001153633.1:p.Lys1439del inframe deletion NM_001354701.2:c.4417AAG[1] NP_001341630.1:p.Lys1474del inframe deletion NM_198056.2:c.4477_4479delAAG NM_198056.3:c.4474AAG[1] NP_932173.1:p.Lys1493del inframe deletion NC_000003.12:g.38555721TCT[1] NC_000003.11:g.38597212TCT[1] NG_008934.1:g.98949AAG[1] LRG_289:g.98949AAG[1] - Protein change
- K1492del, K1493del, K1439del, K1475del, K1474del
- Other names
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- Canonical SPDI
- NC_000003.12:38555718:CTTCTTCT:CTTCT
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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
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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 |
3724 | 4156 |
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
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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Likely pathogenic (1) |
criteria provided, multiple submitters, no conflicts
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Nov 19, 2015 | RCV000208493.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 5, 2020 | RCV003225043.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Dec 29, 2022 | RCV003541541.1 |
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
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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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Likely pathogenic
(Nov 19, 2015)
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criteria provided, single submitter
Method: clinical testing
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Brugada syndrome
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV000264217.2
First in ClinVar: Mar 01, 2016 Last updated: Mar 01, 2016 |
Number of individuals with the variant: 1
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Pathogenic
(Nov 05, 2020)
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criteria provided, single submitter
Method: clinical testing
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Brugada syndrome 1
Affected status: yes
Allele origin:
paternal
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Accession: SCV003921974.1
First in ClinVar: May 06, 2023 Last updated: May 06, 2023 |
Comment:
0103 - Loss of function and gain of function are both known mechanisms of disease in this gene. Loss of function is usually associated with … (more)
0103 - Loss of function and gain of function are both known mechanisms of disease in this gene. Loss of function is usually associated with Brugada syndrome 1 (MIM#601144) and sick sinus syndrome 1 (SSS) (MIM#608567), whereas gain of function is usually associated with long QT syndrome-3 (LQTS) (MIM#603830). Dilated cardiomyopathy 1E (DCM) (MIM#601154) can be caused by variants with either a loss or gain of function mechanism (PMID: 29798782). (I) 0108 - This gene is associated with both recessive and dominant disease. Most conditions associated with this gene are dominantly inherited; however SSS is caused by biallelic variants (OMIM). (I) 0213 - In-frame deletion in a non-repetitive region that has high conservation. (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0600 - Variant is located in the annotated linker region between domains DIII S6 and DIV S1 (PMID: 23840796). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic in ClinVar and observed in multiple heterozygous patients with both Brugada syndrome and atrioventricular conduction disease (PMID: 31231243; 20129283; 19808440; 23840796; 21315837; 14961552). Some patients were described as asymptomatic, and there was a single example of a patient with severe sinus bradycardia, who was compound heterozygous with an additional missense variant. (SP) 0901 - This variant has strong evidence for segregation with disease. This variant segregated within ten individuals from a single family, where all carriers displayed defects on ECG analysis (PMID: 23840796). Additionally, this variant segregated with Brugada syndrome in six individuals from a single family (PMID: 14961552). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Transfected HEK293 cells demonstrated a significant reduction in Na+ current with slowed inactivation and increased time constant, in addition to reduced sarcolemma expression (PMID: 23840796). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Likely pathogenic
(Dec 29, 2022)
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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: SCV002267987.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. Experimental studies have shown that this variant affects SCN5A function (PMID: 23840796, 31231243). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 222814). This variant has been observed in individuals with clinical features of SCN5A-related conditions (PMID: 19808440, 23840796, 30193851). This variant is not present in population databases (gnomAD no frequency). This variant, c.4477_4479del, results in the deletion of 1 amino acid(s) of the SCN5A protein (p.Lys1493del), but otherwise preserves the integrity of the reading frame. (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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Mutations in Na(V)1.5 Reveal Calcium-Calmodulin Regulation of Sodium Channel. | Nof E | Frontiers in physiology | 2019 | PMID: 31231243 |
Clinical presentation and follow-up of women affected by Brugada syndrome. | Berthome P | Heart rhythm | 2019 | PMID: 30193851 |
A heterozygous deletion mutation in the cardiac sodium channel gene SCN5A with loss- and gain-of-function characteristics manifests as isolated conduction disease, without signs of Brugada or long QT syndrome. | Zumhagen S | PloS one | 2013 | PMID: 23840796 |
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 |
Absence of pathognomonic or inflammatory patterns in cardiac biopsies from patients with Brugada syndrome. | Zumhagen S | Circulation. Arrhythmia and electrophysiology | 2009 | PMID: 19808440 |
Text-mined citations for rs869025522 ...
HelpRecord last updated Feb 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.