ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.1858C>T (p.Arg620Cys)
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.1858C>T (p.Arg620Cys)
Variation ID: 67694 Accession: VCV000067694.56
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 38603744 (GRCh38) [ NCBI UCSC ] 3: 38645235 (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 Jun 9, 2014 Sep 16, 2024 Jun 12, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000335.5:c.1858C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000326.2:p.Arg620Cys missense NM_001099404.2:c.1858C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001092874.1:p.Arg620Cys missense NM_001099405.2:c.1858C>T NP_001092875.1:p.Arg620Cys missense NM_001160160.2:c.1858C>T NP_001153632.1:p.Arg620Cys missense NM_001160161.2:c.1858C>T NP_001153633.1:p.Arg620Cys missense NM_001354701.2:c.1858C>T NP_001341630.1:p.Arg620Cys missense NM_198056.3:c.1858C>T NP_932173.1:p.Arg620Cys missense NC_000003.12:g.38603744G>A NC_000003.11:g.38645235G>A NG_008934.1:g.50929C>T LRG_289:g.50929C>T LRG_289t1:c.1858C>T LRG_289p1:p.Arg620Cys Q14524:p.Arg620Cys - Protein change
- R620C
- Other names
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- Canonical SPDI
- NC_000003.12:38603743:G:A
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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.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD) 0.00004
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
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 | 4220 |
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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not provided (1) |
criteria provided, single submitter
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- | RCV000058458.17 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Mar 23, 2023 | RCV001588892.15 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Sep 17, 2023 | RCV001842301.13 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 12, 2024 | RCV004700364.1 |
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
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
(Jun 12, 2024)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005204377.1
First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024 |
Comment:
Variant summary: SCN5A c.1858C>T (p.Arg620Cys) results in a non-conservative amino acid change located in the voltage-gated Na+ ion channel, cytoplasmic domain (IPR024583) of the encoded … (more)
Variant summary: SCN5A c.1858C>T (p.Arg620Cys) results in a non-conservative amino acid change located in the voltage-gated Na+ ion channel, cytoplasmic domain (IPR024583) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.1e-05 in 191644 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1858C>T has been reported in the literature in the heterozyougs state in individuals affected dilated cardiomyopathy, long QT syndrome, and Brugada syndrome (e.g. Hazebroek_2018, Riur_2015, Verdonschot_2020, Berthome_2019). These data do not allow any conclusion about variant significance. Co-occurrences with other pathogenic variant(s) have been reported (KCNQ1 c.760G>A, p.Val254Met), providing supporting evidence for a benign role. At least one in vitro study reports experimental evidence that this variant did not show a dominant negative effect or reduce peak current densities when co-expressed with WT protein (e.g. Hoshi_2014). The following publications have been ascertained in the context of this evaluation (PMID: 20129283, 30193851, 29540472, 24573164, 37288251, 30828412, 24667783, 32880476). ClinVar contains an entry for this variant (Variation ID: 67694). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Jun 08, 2022)
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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: SCV001823318.3
First in ClinVar: Sep 08, 2021 Last updated: Mar 04, 2023 |
Comment:
Functional studies demonstrate that co-expression with wild type did not reduce peak current densities (Hoshi et al., 2014); Reported in association with Brugada syndrome, LQTS, … (more)
Functional studies demonstrate that co-expression with wild type did not reduce peak current densities (Hoshi et al., 2014); Reported in association with Brugada syndrome, LQTS, and DCM (Kapplinger et al., 2010; Hazebroek et al., 2015; Kapplinger et al., 2015; Kroncke et al., 2018; Berthome et al., 2019; Verdonschot et al., 2020); Identified in a proband and two siblings with LQTS; all three individuals also harbored a pathogenic KCNQ1 variant (Riur et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30193851, 32880476, 20129283, 24573164, 26383716, 29728395, 30662450, 24667783, 25904541) (less)
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Uncertain significance
(Sep 07, 2023)
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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: SCV000905121.3
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with cysteine at codon 620 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces arginine with cysteine at codon 620 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). Functional studies have shown that this variant does not cause a reduction in peak current densities when co-expressed with a wild type protein (PMID: 24573164). This variant has been reported in an individual suspected of having Brugada syndrome (PMID: 20129283). This variant has also been observed in three individuals in a family affected with Long QT syndrome (PMID: 24667783). However, all of these individuals carried a pathogenic variant in KCNQ1, suggesting that this SCN5A variant was likely not the primary cause of disease. This variant has been identified in 7/223000 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
(Mar 23, 2023)
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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: SCV000637091.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 620 of the SCN5A protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 620 of the SCN5A protein (p.Arg620Cys). 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. Experimental studies have shown that this missense change affects SCN5A function (PMID: 24573164, 25904541). 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 67694). This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 20129283, 24667783, 29728395, 30193851, 32880476). This variant is present in population databases (rs199473577, gnomAD 0.01%). (less)
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Uncertain Significance
(Sep 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiac arrhythmia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004818629.1
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)
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Comment:
This missense variant replaces arginine with cysteine at codon 620 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces arginine with cysteine at codon 620 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). Functional studies have shown that this variant does not cause a reduction in peak current densities when co-expressed with a wild type protein (PMID: 24573164). This variant has been reported in an individual suspected of having Brugada syndrome (PMID: 20129283). This variant has also been observed in three individuals in a family affected with Long QT syndrome (PMID: 24667783). However, all of these individuals carried a pathogenic variant in KCNQ1, suggesting that this SCN5A variant was likely not the primary cause of disease. This variant has been identified in 7/223000 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: 2
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not provided
(-)
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no classification provided
Method: literature only
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Brugada syndrome
Affected status: unknown
Allele origin:
germline
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Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust
Accession: SCV000089978.3
First in ClinVar: Oct 22, 2013 Last updated: Jun 09, 2014 |
Comment:
This variant has been reported as associated with Brugada syndrome in the following publications (PMID:20129283). This is a literature report, and does not necessarily reflect … (more)
This variant has been reported as associated with Brugada syndrome in the following publications (PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. (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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Single coronary artery presenting dilated cardiomyopathy and hyperlipidemia with the SCN5A and APOA5 gene mutation: A case report and review of the literature. | Hu X | Frontiers in cardiovascular medicine | 2023 | PMID: 37288251 |
Implications of Genetic Testing in Dilated Cardiomyopathy. | Verdonschot JAJ | Circulation. Genomic and precision medicine | 2020 | PMID: 32880476 |
Protein structure aids predicting functional perturbation of missense variants in SCN5A and KCNQ1. | Kroncke BM | Computational and structural biotechnology journal | 2019 | PMID: 30828412 |
Clinical presentation and follow-up of women affected by Brugada syndrome. | Berthome P | Heart rhythm | 2019 | PMID: 30193851 |
SCN5A (Na(V)1.5) Variant Functional Perturbation and Clinical Presentation: Variants of a Certain Significance. | Kroncke BM | Circulation. Genomic and precision medicine | 2018 | PMID: 29728395 |
Prevalence of Pathogenic Gene Mutations and Prognosis Do Not Differ in Isolated Left Ventricular Dysfunction Compared With Dilated Cardiomyopathy. | Hazebroek MR | Circulation. Heart failure | 2018 | PMID: 29540472 |
Enhanced Classification of Brugada Syndrome-Associated and Long-QT Syndrome-Associated Genetic Variants in the SCN5A-Encoded Na(v)1.5 Cardiac Sodium Channel. | Kapplinger JD | Circulation. Cardiovascular genetics | 2015 | PMID: 25904541 |
Genetic analysis, in silico prediction, and family segregation in long QT syndrome. | Riuró H | European journal of human genetics : EJHG | 2015 | PMID: 24667783 |
Brugada syndrome disease phenotype explained in apparently benign sodium channel mutations. | Hoshi M | Circulation. Cardiovascular genetics | 2014 | PMID: 24573164 |
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 rs199473577 ...
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.