ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.1579G>A (p.Gly527Arg)
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
-
NM_000335.5(SCN5A):c.1579G>A (p.Gly527Arg)
Variation ID: 406447 Accession: VCV000406447.15
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3p22.2 3: 38604023 (GRCh38) [ NCBI UCSC ] 3: 38645514 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 17, 2017 Sep 16, 2024 Jan 11, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000335.5:c.1579G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000326.2:p.Gly527Arg missense NM_001099404.2:c.1579G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001092874.1:p.Gly527Arg missense NM_001099405.2:c.1579G>A NP_001092875.1:p.Gly527Arg missense NM_001160160.2:c.1579G>A NP_001153632.1:p.Gly527Arg missense NM_001160161.2:c.1579G>A NP_001153633.1:p.Gly527Arg missense NM_001354701.2:c.1579G>A NP_001341630.1:p.Gly527Arg missense NM_198056.3:c.1579G>A NP_932173.1:p.Gly527Arg missense NC_000003.12:g.38604023C>T NC_000003.11:g.38645514C>T NG_008934.1:g.50650G>A LRG_289:g.50650G>A LRG_289t1:c.1579G>A LRG_289p1:p.Gly527Arg - Protein change
- G527R
- Other names
- -
- Canonical SPDI
- NC_000003.12:38604022:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00003
Exome Aggregation Consortium (ExAC) 0.00004
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 | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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. |
|||
SCN5A | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3779 | 4220 |
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
Help
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. |
---|---|---|---|---|
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Dec 12, 2023 | RCV000589940.14 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 11, 2024 | RCV001841361.13 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Apr 6, 2022 | RCV002402244.9 |
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. |
|
---|---|---|---|---|---|
Uncertain significance
(Sep 19, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000700019.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The SCN5A c.1579G>A (p.Gly527Arg) variant involves the alteration of a non-conserved nucleotide. This variant is located in the voltage-gated Na+ ion channel cytoplasmic … (more)
Variant summary: The SCN5A c.1579G>A (p.Gly527Arg) variant involves the alteration of a non-conserved nucleotide. This variant is located in the voltage-gated Na+ ion channel cytoplasmic domain (InterPro). 3/3 in silico tools predict a damaging outcome for this variant. This variant was found in 4/90200 control chromosomes at a frequency of 0.0000443, which is approximately 2 times the estimated maximal expected allele frequency of a pathogenic SCN5A variant (0.000025), suggesting this variant is possibly a benign polymorphism. However, with only four heterozygotes in ExAC it is uncertain whether this variant is benign as the phenotypes linked with this gene is often silent and has a variable age of onset and the pathogenic variants in this gene could have a reduced penetrance. The variant of interest has been reported in at least 1 affected individual without strong evidence for causality (Kapoor, 2016) and in 1 unaffected control from case-control studiy (Le Scouarnec,2015). It has been reported in a kidney carcinoma sample (Pickering CR et al 2014) and a skin carcinoma sample as a somatic occurrence (COSMIC). The variant has not been evaluated for functional impact by in vivo/vitro studies. Additional supporting evidence needed to classify this variant with confidence. Taken together, this variant is classified as variant of uncertain significance. (less)
|
|
Uncertain significance
(Jul 19, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000545099.5
First in ClinVar: Apr 17, 2017 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 527 of the SCN5A protein (p.Gly527Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 527 of the SCN5A protein (p.Gly527Arg). This variant is present in population databases (rs763550164, gnomAD 0.02%). 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 406447). This missense change has been observed in individual(s) with SCN5A-related conditions (Invitae). (less)
|
|
Uncertain significance
(Apr 07, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiac arrhythmia
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV001354470.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces glycine with arginine at codon 527 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces glycine with arginine at codon 527 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Brugada syndrome (PMID: 32268277), an individual suspected of having Brugada syndrome (PMID: 29309564), and an individual suspected of having epilepsy (PMID: 31696929). This variant has also been identified in 8/243942 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)
|
|
Uncertain significance
(Apr 06, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002710086.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.G527R variant (also known as c.1579G>A), located in coding exon 11 of the SCN5A gene, results from a G to A substitution at nucleotide … (more)
The p.G527R variant (also known as c.1579G>A), located in coding exon 11 of the SCN5A gene, results from a G to A substitution at nucleotide position 1579. The glycine at codon 527 is replaced by arginine, an amino acid with dissimilar properties. This variant has been detected in individuals from cohorts with various phenotypes including suspected Brugada syndrome, suspected epilepsy, and spastic ataxia; however, clinical details were limited and some cases had additional variants in SCN5A or other genes (Lu Q et al. Ann Transl Med, 2020 Jan;8:8; Campuzano O et al. EBioMedicine, 2020 Apr;54:102732; Li X et al. Ann Hum Genet, 2020 03;84:161-168; Pablo Flórez J et al. Europace, 2018 06;20:f64-f71). This variant has also been detected in a control cohort and a study of variants associated with QT interval; however, details were limited (Kapoor A et al. Sci Rep, 2016 06;6:28356; Le Scouarnec S et al. Hum Mol Genet, 2015 May;24:2757-63). This amino acid position is well 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)
|
|
Uncertain significance
(Dec 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000589468.3
First in ClinVar: Aug 20, 2017 Last updated: Sep 16, 2024 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25650408, 27321809) (less)
|
|
Uncertain Significance
(Jan 11, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiac arrhythmia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004817130.1
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)
|
Comment:
This missense variant replaces glycine with arginine at codon 527 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces glycine with arginine at codon 527 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Brugada syndrome (PMID: 32268277), an individual suspected of having Brugada syndrome (PMID: 29309564), and an individual suspected of having epilepsy (PMID: 31696929). This variant has also been identified in 8/243942 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)
Number of individuals with the variant: 8
|
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 |
---|---|---|---|---|
Reanalysis and reclassification of rare genetic variants associated with inherited arrhythmogenic syndromes. | Campuzano O | EBioMedicine | 2020 | PMID: 32268277 |
Complicated paroxysmal kinesigenic dyskinesia associated with SACS mutations. | Lu Q | Annals of translational medicine | 2020 | PMID: 32055599 |
Variant frequencies of KCNQ1, KCNH2, and SCN5A in a Chinese inherited arrhythmia cohort and other disease cohorts undergoing genetic testing. | Li X | Annals of human genetics | 2020 | PMID: 31696929 |
Role of syncope in predicting adverse outcomes in patients with suspected Brugada syndrome undergoing standardized flecainide testing. | Pablo Flórez J | Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology | 2018 | PMID: 29309564 |
Rare coding TTN variants are associated with electrocardiographic QT interval in the general population. | Kapoor A | Scientific reports | 2016 | PMID: 27321809 |
Testing the burden of rare variation in arrhythmia-susceptibility genes provides new insights into molecular diagnosis for Brugada syndrome. | Le Scouarnec S | Human molecular genetics | 2015 | PMID: 25650408 |
Text-mined citations for rs763550164 ...
HelpRecord last updated Oct 13, 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.