ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.4856C>T (p.Thr1619Met)
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.4856C>T (p.Thr1619Met)
Variation ID: 67932 Accession: VCV000067932.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 38551513 (GRCh38) [ NCBI UCSC ] 3: 38593004 (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 Feb 20, 2024 Jan 8, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000335.5:c.4856C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000326.2:p.Thr1619Met missense NM_001099404.2:c.4859C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001092874.1:p.Thr1620Met missense NM_001099405.2:c.4805C>T NP_001092875.1:p.Thr1602Met missense NM_001160160.2:c.4760C>T NP_001153632.1:p.Thr1587Met missense NM_001160161.2:c.4697C>T NP_001153633.1:p.Thr1566Met missense NM_001354701.2:c.4802C>T NP_001341630.1:p.Thr1601Met missense NM_198056.3:c.4859C>T NP_932173.1:p.Thr1620Met missense NC_000003.12:g.38551513G>A NC_000003.11:g.38593004G>A NG_008934.1:g.103160C>T LRG_289:g.103160C>T LRG_289t1:c.4859C>T LRG_289t2:c.4856C>T Q14524:p.Thr1620Met - Protein change
- T1620M, T1619M, T1566M, T1587M, T1601M, T1602M
- Other names
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- Canonical SPDI
- NC_000003.12:38551512: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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
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 |
3557 | - |
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. |
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not provided (1) |
criteria provided, single submitter
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- | RCV000058715.15 | |
Likely pathogenic (2) |
criteria provided, single submitter
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Jun 15, 2022 | RCV000144031.13 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 8, 2024 | RCV001836727.11 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 28, 2021 | RCV001842371.11 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jul 1, 2021 | RCV002477202.8 |
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. |
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Likely pathogenic
(Jun 15, 2022)
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criteria provided, single submitter
Method: clinical testing
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Brugada syndrome 1
Affected status: unknown
Allele origin:
germline
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Institute of Human Genetics, Heidelberg University
Accession: SCV002757810.1
First in ClinVar: Dec 03, 2022 Last updated: Dec 03, 2022 |
Comment:
reported as secondary finding
Sex: female
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Likely pathogenic
(Jul 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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Progressive familial heart block, type 1A
SUDDEN INFANT DEATH SYNDROME Brugada syndrome 1 Dilated cardiomyopathy 1E Ventricular fibrillation, paroxysmal familial, type 1 Long QT syndrome 3 Sick sinus syndrome 1 Atrial fibrillation, familial, 10
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002797462.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Likely pathogenic
(Feb 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: SCV002097418.2
First in ClinVar: Feb 20, 2022 Last updated: Mar 04, 2023 |
Comment:
Multiple studies have examined the functional effect of the T1620M variant, with the general conclusion that this variant impacts sodium ion channel function (Chen et … (more)
Multiple studies have examined the functional effect of the T1620M variant, with the general conclusion that this variant impacts sodium ion channel function (Chen et al., 1998; Dumaine et al., 1999; Makita et al., 2000; Shirai et al., 2002); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11786529, 11827685, 10618304, 11013131, 23785128, 29728395, 30662450, 30847666, 15520322, 20129283, 10532948, 11029409, 11123251, 9521325, 34135346, 33131149) (less)
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Likely pathogenic
(Sep 28, 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: SCV001340219.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces threonine with methionine at codon 1620 in the transmembrane domain DIV of the SCN5A protein. Computational prediction suggests that this variant … (more)
This missense variant replaces threonine with methionine at codon 1620 in the transmembrane domain DIV of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Multiple functional studies have generally shown that this variant alters the sodium channel function (PMID: 9521325, 10532948, 10618304, 11029409, 11123251, 11827685, 30050137). This variant has been reported in multiple unrelated individuals affected with Brugada syndrome (PMID: 15520322, 20129283, 25904541) and has been shown to segregate with disease in six relatives from a family (PMID: 9521325, 10662748, 15520322). This variant has been identified in 1/250918 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
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Pathogenic
(Jan 08, 2024)
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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: SCV000637164.5
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1620 of the SCN5A protein (p.Thr1620Met). … (more)
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1620 of the SCN5A protein (p.Thr1620Met). This variant is present in population databases (rs199473282, gnomAD 0.0009%). This missense change has been observed in individual(s) with Brugada syndrome and/or clinical features of SCN5A-related conditions (PMID: 9521325, 15520322, 20129283, 23785128, 29728395, 30847666, 34076677). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 67932). 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. Experimental studies have shown that this missense change affects SCN5A function (PMID: 9521325, 10532948, 10618304, 11029409, 11123251, 11827685). For these reasons, this variant has been classified as Pathogenic. (less)
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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: SCV000090235.3
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:9521325;PMID:20129283;PMID:10618304;PMID:15520322;PMID:11013131). 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:9521325;PMID:20129283;PMID:10618304;PMID:15520322;PMID:11013131). 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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not provided
(-)
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no classification provided
Method: literature only
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Brugada syndrome 1
Affected status: yes
Allele origin:
germline
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GeneReviews
Accession: SCV000188924.3
First in ClinVar: Sep 11, 2014 Last updated: Oct 01, 2022 |
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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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Brugada Syndrome. | Adam MP | - | 2022 | PMID: 20301690 |
Genetic Variants Associated With Unexplained Sudden Cardiac Death in Adult White and African American Individuals. | Guo L | JAMA cardiology | 2021 | PMID: 34076677 |
Large next-generation sequencing gene panels in genetic heart disease: yield of pathogenic variants and variants of unknown significance. | van Lint FHM | Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation | 2019 | PMID: 30847666 |
Identification of an I(Na)-dependent and I(to)-mediated proarrhythmic mechanism in cardiomyocytes derived from pluripotent stem cells of a Brugada syndrome patient. | Ma D | Scientific reports | 2018 | PMID: 30050137 |
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 |
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 |
Targeted sequence capture and GS-FLX Titanium sequencing of 23 hypertrophic and dilated cardiomyopathy genes: implementation into diagnostics. | Mook OR | Journal of medical genetics | 2013 | PMID: 23785128 |
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 |
Value of electrocardiographic parameters and ajmaline test in the diagnosis of Brugada syndrome caused by SCN5A mutations. | Hong K | Circulation | 2004 | PMID: 15520322 |
A mutant cardiac sodium channel with multiple biophysical defects associated with overlapping clinical features of Brugada syndrome and cardiac conduction disease. | Shirai N | Cardiovascular research | 2002 | PMID: 11827685 |
Accelerated inactivation in a mutant Na(+) channel associated with idiopathic ventricular fibrillation. | Wan X | American journal of physiology. Heart and circulatory physiology | 2001 | PMID: 11123251 |
Enhanced Na(+) channel intermediate inactivation in Brugada syndrome. | Wang DW | Circulation research | 2000 | PMID: 11029409 |
Functional suppression of sodium channels by beta(1)-subunits as a molecular mechanism of idiopathic ventricular fibrillation. | Wan X | Journal of molecular and cellular cardiology | 2000 | PMID: 11013131 |
Sodium channel blockers identify risk for sudden death in patients with ST-segment elevation and right bundle branch block but structurally normal hearts. | Brugada R | Circulation | 2000 | PMID: 10662748 |
Cardiac Na(+) channel dysfunction in Brugada syndrome is aggravated by beta(1)-subunit. | Makita N | Circulation | 2000 | PMID: 10618304 |
Ionic mechanisms responsible for the electrocardiographic phenotype of the Brugada syndrome are temperature dependent. | Dumaine R | Circulation research | 1999 | PMID: 10532948 |
Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. | Chen Q | Nature | 1998 | PMID: 9521325 |
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Text-mined citations for rs199473282 ...
HelpRecord last updated Apr 15, 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.