ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.3061C>T (p.Pro1021Ser)
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.3061C>T (p.Pro1021Ser)
Variation ID: 201484 Accession: VCV000201484.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 38581098 (GRCh38) [ NCBI UCSC ] 3: 38622589 (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 Apr 8, 2017 May 1, 2024 Oct 23, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000335.5:c.3061C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000326.2:p.Pro1021Ser missense NM_001099404.2:c.3061C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001092874.1:p.Pro1021Ser missense NM_001099405.2:c.3061C>T NP_001092875.1:p.Pro1021Ser missense NM_001160160.2:c.3061C>T NP_001153632.1:p.Pro1021Ser missense NM_001160161.2:c.3061C>T NP_001153633.1:p.Pro1021Ser missense NM_001354701.2:c.3061C>T NP_001341630.1:p.Pro1021Ser missense NM_198056.3:c.3061C>T NP_932173.1:p.Pro1021Ser missense NC_000003.12:g.38581098G>A NC_000003.11:g.38622589G>A NG_008934.1:g.73575C>T NG_053884.1:g.2837G>A LRG_289:g.73575C>T LRG_289t1:c.3061C>T LRG_289p1:p.Pro1021Ser - Protein change
- P1021S
- Other names
- p.P1021S:CCC>TCC
- Canonical SPDI
- NC_000003.12:38581097: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.
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
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 |
3739 | 4175 | |
LOC110121269 | - | - | - | GRCh38 | - | 417 |
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 (1) |
criteria provided, single submitter
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Oct 20, 2016 | RCV000183017.17 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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May 30, 2023 | RCV000766796.11 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Oct 23, 2023 | RCV001842909.13 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 25, 2022 | RCV002444735.9 |
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
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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
(Oct 20, 2016)
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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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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000540289.1
First in ClinVar: Apr 08, 2017 Last updated: Apr 08, 2017 |
Comment:
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or … (more)
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 1 report: Can't access supplement where variant is referenced, but no sign that there would be segregation data anyway. Insufficient evidence to go above VUS. (less)
Method: Genome/Exome Filtration
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Uncertain significance
(Jun 23, 2021)
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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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AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002501542.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
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Uncertain significance
(Sep 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: SCV001356474.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This variant replaces proline with serine at codon 1021 in the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein … (more)
This variant replaces proline with serine at codon 1021 in 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 individuals affected with long QT syndrome (PMID: 23174487, 27566755). This variant has been identified in 3/247684 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
(Apr 25, 2022)
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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: SCV002753619.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.P1021S variant (also known as c.3061C>T), located in coding exon 16 of the SCN5A gene, results from a C to T substitution at nucleotide … (more)
The p.P1021S variant (also known as c.3061C>T), located in coding exon 16 of the SCN5A gene, results from a C to T substitution at nucleotide position 3061. The proline at codon 1021 is replaced by serine, an amino acid with similar properties. This alteration has been reported in long QT syndrome cohorts (Mullally J et al. Heart Rhythm, 2013 Mar;10:378-82; Wilde AA et al. Circulation, 2016 Sep;134:872-82). This amino acid position is not 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)
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Uncertain significance
(Feb 08, 2017)
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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: SCV000235425.13
First in ClinVar: Jul 05, 2015 Last updated: Apr 17, 2019 |
Comment:
The P1021S variant has been reported in one individual with LQTS (Mullally et al., 2013), though no clinical or segregation data was provided. The P1021S … (more)
The P1021S variant has been reported in one individual with LQTS (Mullally et al., 2013), though no clinical or segregation data was provided. The P1021S variant was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Although P1021S has been seen in multiple individuals referred for LQTS testing at GeneDx, segregation data is not sufficient due to the lack of clinical information provided and/or insufficient participation by informative family members. The P1021S variant, located in the DII/DIII intracellular loop, results in 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. However, this substitution occurs at a position that is not conserved. Consequently, in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. (less)
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Uncertain significance
(May 30, 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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Invitae
Accession: SCV001494310.3
First in ClinVar: Mar 07, 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. 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: 201484). This missense change has been observed in individual(s) with clinical features of long QT syndrome (PMID: 23174487). This variant is present in population databases (rs794728871, gnomAD 0.003%). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1021 of the SCN5A protein (p.Pro1021Ser). (less)
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Uncertain Significance
(Oct 23, 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: SCV004836772.1
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 variant replaces proline with serine at codon 1021 in the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein … (more)
This variant replaces proline with serine at codon 1021 in 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 individuals affected with long QT syndrome (PMID: 23174487, 27566755). This variant has been identified in 3/247684 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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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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Retrospective Genetic Analysis of 200 Cases of Sudden Infant Death Syndrome and Its Relationship with Long QT Syndrome in Korea. | Son MJ | Journal of Korean medical science | 2018 | PMID: 30079003 |
Clinical Aspects of Type 3 Long-QT Syndrome: An International Multicenter Study. | Wilde AA | Circulation | 2016 | PMID: 27566755 |
Risk of life-threatening cardiac events among patients with long QT syndrome and multiple mutations. | Mullally J | Heart rhythm | 2013 | PMID: 23174487 |
Text-mined citations for rs794728871 ...
HelpRecord last updated May 12, 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.