ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.1538G>C (p.Arg513Pro)
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.1538G>C (p.Arg513Pro)
Variation ID: 532073 Accession: VCV000532073.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 38604064 (GRCh38) [ NCBI UCSC ] 3: 38645555 (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 May 28, 2018 Sep 1, 2024 Sep 1, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000335.5:c.1538G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000326.2:p.Arg513Pro missense NM_001099404.2:c.1538G>C MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001092874.1:p.Arg513Pro missense NM_001099405.2:c.1538G>C NP_001092875.1:p.Arg513Pro missense NM_001160160.2:c.1538G>C NP_001153632.1:p.Arg513Pro missense NM_001160161.2:c.1538G>C NP_001153633.1:p.Arg513Pro missense NM_001354701.2:c.1538G>C NP_001341630.1:p.Arg513Pro missense NM_198056.3:c.1538G>C NP_932173.1:p.Arg513Pro missense NC_000003.12:g.38604064C>G NC_000003.11:g.38645555C>G NG_008934.1:g.50609G>C LRG_289:g.50609G>C LRG_289t1:c.1538G>C LRG_289p1:p.Arg513Pro - Protein change
- R513P
- Other names
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- Canonical SPDI
- NC_000003.12:38604063:C:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- functionally_normal Sequence Ontology [SO:0002219]
- No RNA splicing impact [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
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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 |
3773 | 4212 |
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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Uncertain significance (1) |
criteria provided, single submitter
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Sep 1, 2021 | RCV000638674.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 18, 2021 | RCV001841833.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 30, 2020 | RCV002404786.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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- | RCV004698507.1 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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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Uncertain significance
(Feb 18, 2021)
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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: SCV001358619.2
First in ClinVar: Jun 22, 2020 Last updated: Jun 19, 2021 |
Comment:
This missense variant replaces arginine with proline at codon 513 of the SCN5A protein. Computational prediction tool suggests that this variant may not impact protein … (more)
This missense variant replaces arginine with proline at codon 513 of the SCN5A protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold ≤0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in one individual affected with dilated cardiomyopathy (PMID: 32659924). This variant has been identified in 1/230892 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Sep 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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Brugada syndrome
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000760213.2
First in ClinVar: May 28, 2018 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces arginine with proline at codon 513 of the SCN5A protein (p.Arg513Pro). The arginine residue is weakly conserved and there is a … (more)
This sequence change replaces arginine with proline at codon 513 of the SCN5A protein (p.Arg513Pro). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. 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 tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Oct 30, 2020)
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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: SCV002705035.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.R513P variant (also known as c.1538G>C), located in coding exon 11 of the SCN5A gene, results from a G to C substitution at nucleotide … (more)
The p.R513P variant (also known as c.1538G>C), located in coding exon 11 of the SCN5A gene, results from a G to C substitution at nucleotide position 1538. The arginine at codon 513 is replaced by proline, an amino acid with dissimilar properties, and is located in the DI/DII interdomain linker region. This variant has been detected in an individual from a dilated cardiomyopathy cohort; however, detail was limited (Kolokotronis K et al. J Clin Med, 2020 Jul;9). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(-)
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criteria provided, single submitter
Method: research, in vitro
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Brugada syndrome 1
Affected status: unknown, not applicable
Allele origin:
germline,
not applicable
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Roden Lab, Vanderbilt University Medical Center
Accession: SCV005200444.1
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, 3-38604064-C-G 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 0.2095; 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 VUS using these collective data. (less)
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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, 3-38604064-C-G 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 0.2095; 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 VUS 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:
No RNA splicing impact
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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
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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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functionally_normal
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Method citation(s):
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Roden Lab, Vanderbilt University Medical Center
Accession: SCV005200444.1
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Comment:
No RNA splicing impact
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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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 |
New Insights on Genetic Diagnostics in Cardiomyopathy and Arrhythmia Patients Gained by Stepwise Exome Data Analysis. | Kolokotronis K | Journal of clinical medicine | 2020 | PMID: 32659924 |
Text-mined citations for rs397517951 ...
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.