ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.1990A>G (p.Ser664Gly)
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.1990A>G (p.Ser664Gly)
Variation ID: 449199 Accession: VCV000449199.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 38598951 (GRCh38) [ NCBI UCSC ] 3: 38640442 (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 Dec 19, 2017 May 1, 2024 Feb 5, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000335.5:c.1990A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000326.2:p.Ser664Gly missense NM_001099404.2:c.1990A>G MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001092874.1:p.Ser664Gly missense NM_001099405.2:c.1990A>G NP_001092875.1:p.Ser664Gly missense NM_001160160.2:c.1990A>G NP_001153632.1:p.Ser664Gly missense NM_001160161.2:c.1990A>G NP_001153633.1:p.Ser664Gly missense NM_001354701.2:c.1990A>G NP_001341630.1:p.Ser664Gly missense NM_198056.3:c.1990A>G NP_932173.1:p.Ser664Gly missense NC_000003.12:g.38598951T>C NC_000003.11:g.38640442T>C NG_008934.1:g.55722A>G LRG_289:g.55722A>G LRG_289t1:c.1990A>G LRG_289p1:p.Ser664Gly - Protein change
- S664G
- Other names
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- Canonical SPDI
- NC_000003.12:38598950:T:C
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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) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
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 | ||
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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 |
3779 | 4220 |
Conditions - Germline
Condition
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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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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Oct 4, 2022 | RCV000523591.11 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Feb 5, 2024 | RCV001841410.13 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 3, 2023 | RCV004023536.1 |
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
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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
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
(Aug 29, 2016)
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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: SCV000617044.2
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
Comment:
A variant of uncertain significance has been identified in the SCN5A gene. The S664G variant has not been published as a pathogenic variant, nor has … (more)
A variant of uncertain significance has been identified in the SCN5A gene. The S664G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, this variant has been observed in one other unrelated individual referred for LQTS genetic testing at GeneDx. S664G was not observed in approximately 6,500 individuals of European and African American ancestry in an external variant database, indicating it is not a common benign variant in these populations. The S664G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In silico analysis predicts this variant is probably damaging to the protein structure/function. This substitution occurs at a position in the cytoplasmic linker between DI and DII of the protein that is conserved across species. Biochemical analysis of Nav1.5 protein (encoded by the SCN5A gene) isolated from adult mouse ventricular cardiomyocytes showed that the S664 residue is phosphorylated in situ; however, the functional significance of this phosphorylation remains to be elucidated (Marionneau et al., 2012). Although missense variants in nearby residues (A662S, A665S) have been reported in the Human Gene Mutation Database in association with sudden unexplained death and LQTS (Stenson et al., 2014), the pathogenicity of these variants has not been definitively determined. Furthermore, to our knowledge no studies have been performed to determine the functional effect of the S664G variant.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign. (less)
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Uncertain significance
(May 15, 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: SCV001359802.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces serine with glycine at codon 664 of the SCN5A protein. Computational prediction suggests that this variant may have a deleterious impact … (more)
This missense variant replaces serine with glycine at codon 664 of the SCN5A protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with SCN5A-related disorders in the literature. This variant has been identified in 2/249028 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
(Oct 04, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001508318.3
First in ClinVar: Mar 14, 2021 Last updated: Feb 28, 2024 |
Comment:
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 … (more)
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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C55"). ClinVar contains an entry for this variant (Variation ID: 449199). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. This variant is present in population databases (rs757444820, gnomAD 0.002%). This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 664 of the SCN5A protein (p.Ser664Gly). (less)
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Uncertain Significance
(Feb 05, 2024)
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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: SCV004828354.1
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 serine with glycine at codon 664 of the SCN5A protein. Computational prediction suggests that this variant may have a deleterious impact … (more)
This missense variant replaces serine with glycine at codon 664 of the SCN5A protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with SCN5A-related disorders in the literature. This variant has been identified in 2/249028 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: 4
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Uncertain significance
(Nov 03, 2023)
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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: SCV005031238.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
The p.S664G variant (also known as c.1990A>G), located in coding exon 12 of the SCN5A gene, results from an A to G substitution at nucleotide … (more)
The p.S664G variant (also known as c.1990A>G), located in coding exon 12 of the SCN5A gene, results from an A to G substitution at nucleotide position 1990. The serine at codon 664 is replaced by glycine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (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
HelpThere are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar. |
Text-mined citations for rs757444820 ...
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.