ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.5347G>A (p.Glu1783Lys)
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.5347G>A (p.Glu1783Lys)
Variation ID: 9377 Accession: VCV000009377.48
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 38551022 (GRCh38) [ NCBI UCSC ] 3: 38592513 (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 Oct 11, 2015 Apr 15, 2024 Jan 28, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000335.5:c.5347G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000326.2:p.Glu1783Lys missense NM_001099404.2:c.5350G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001092874.1:p.Glu1784Lys missense NM_001099405.2:c.5296G>A NP_001092875.1:p.Glu1766Lys missense NM_001160160.2:c.5251G>A NP_001153632.1:p.Glu1751Lys missense NM_001160161.2:c.5188G>A NP_001153633.1:p.Glu1730Lys missense NM_001354701.2:c.5293G>A NP_001341630.1:p.Glu1765Lys missense NM_198056.3:c.5350G>A NP_932173.1:p.Glu1784Lys missense NC_000003.12:g.38551022C>T NC_000003.11:g.38592513C>T NG_008934.1:g.103651G>A LRG_289:g.103651G>A LRG_289t1:c.5350G>A LRG_289p1:p.Glu1784Lys LRG_289t3:c.5350G>A Q14524:p.Glu1784Lys - Protein change
- E1784K, E1783K, E1751K, E1765K, E1730K, E1766K
- Other names
- p.E1784K:GAG>AAG
- Canonical SPDI
- NC_000003.12:38551021:C:T
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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.
Trans-Omics for Precision Medicine (TOPMed) 0.00002
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
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. |
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SCN5A | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3557 | 3958 |
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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Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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May 28, 2020 | RCV000009972.8 | |
Pathogenic (1) |
no assertion criteria provided
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Jun 1, 2008 | RCV000009973.5 | |
Pathogenic (1) |
no assertion criteria provided
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Jun 1, 2008 | RCV000009974.3 | |
not provided (1) |
no classification provided
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- | RCV000058773.4 | |
Pathogenic (9) |
criteria provided, multiple submitters, no conflicts
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Jan 28, 2024 | RCV000183117.32 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 14, 2022 | RCV000208193.15 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 18, 2021 | RCV000245905.4 | |
Pathogenic (1) |
criteria provided, single submitter
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May 10, 2016 | RCV000588022.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 8, 2016 | RCV000824758.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 5, 2022 | RCV001813738.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 1, 2023 | RCV003591625.1 | |
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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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Pathogenic
(Jul 22, 2015)
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criteria provided, single submitter
Method: clinical testing
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Brugada syndrome
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV000264215.2
First in ClinVar: Mar 01, 2016 Last updated: Oct 10, 2018 |
Number of individuals with the variant: 2
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Pathogenic
(May 10, 2016)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome 1
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000700038.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The SCN5A c.5350G>A (p.Glu1784Lys) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome (SNPs&GO not captured … (more)
Variant summary: The SCN5A c.5350G>A (p.Glu1784Lys) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome (SNPs&GO not captured due to low reliability index). This variant is absent in 121222 control chromosomes, but has been reported in the literature in numerous affected individuals, including patients with both LQTS and Brugada syndrome. In functional studies, the variant showed a persistent inward sodium current, which has also been previously observed as a functional defect in other LQTS SCN5A mutations (Wei_1999, Deschenes_2000). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
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Likely pathogenic
(Oct 15, 2018)
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criteria provided, single submitter
Method: curation
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Long QT syndrome 3
Affected status: unknown
Allele origin:
unknown
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SIB Swiss Institute of Bioinformatics
Accession: SCV000883206.1
First in ClinVar: Nov 18, 2016 Last updated: Nov 18, 2016 |
Comment:
This variant is interpreted as Likely Pathogenic, for Long QT syndrome 3, autosomal dominant. The following ACMG Tag(s) were applied: PM2 => Absent from controls … (more)
This variant is interpreted as Likely Pathogenic, for Long QT syndrome 3, autosomal dominant. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS3 => Well-established functional studies show a deleterious effect. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. (less)
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Pathogenic
(Jul 08, 2016)
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criteria provided, single submitter
Method: clinical testing
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Brugada syndrome
Congenital long QT syndrome (Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000711786.2
First in ClinVar: Apr 09, 2018 Last updated: Aug 26, 2019 |
Comment:
The p.Glu1784Lys variant in SCN5A has been previously reported in >20 individual s with prolonged QT intervals, Long QT syndrome (LQTS), and/or Brugada syndrome , … (more)
The p.Glu1784Lys variant in SCN5A has been previously reported in >20 individual s with prolonged QT intervals, Long QT syndrome (LQTS), and/or Brugada syndrome , including 1 de novo occurrence (Wei 1999, Makita 2008, Deschenes 2000, Nakajim a 2011, Takahashi 2014). Furthermore, the variant segregated with disease in man y affected relatives (LQTS, Brugada syndrome, or prolonged QT intervals; Makita 2008, Wei 1999, Deschenes 2000, Shim 2005, Veltmann 2016). This variant has also been classified by other clinical laboratories as pathogenic in ClinVar (Variat ion ID: 9377) and has been identified in 1/111718 of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). In vitr o functional studies provide some evidence that the p.Glu1784Lys variant may imp act protein function (Deschenes 2000, Makita 2008). In summary, this variant mee ts criteria to be classified as pathogenic for LQTS and Brugada syndrome in an a utosomal dominant manner based upon presence in multiple affected individuals, s egregation studies, very low frequency in controls and functional studies. ACMG/ AMP criteria applied: PS4_Strong; PP1_Strong; PS3_Supporting, PM2. (less)
Number of individuals with the variant: 12
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Pathogenic
(Jan 14, 2022)
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criteria provided, single submitter
Method: clinical testing
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Brugada syndrome
Affected status: yes
Allele origin:
germline
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Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals
Accession: SCV002754558.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
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Pathogenic
(May 26, 2020)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome 3
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002767128.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 5 - Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are … (more)
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 5 - Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene (PMID: 29806494). (N) 0108 - This gene is known to be associated with both recessive and dominant disease (OMIM). (N) 0200 - Variant is predicted to result in a missense amino acid change from a glutamic acid to a lysine (exon 28). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This is a well-reported variant associated with Brugada syndrome and long QT syndrome type 3 (ClinVar, PMID: 20129283; 27381756). (P) 1002 - Moderate functional evidence supporting abnormal protein function. Functional studies have shown that mutant channels demonstrate faster current decay and increased persistent current compared to wild type channels (PMID:18451998). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign (less)
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Pathogenic
(Jan 28, 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: SCV000291817.10
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1784 of the SCN5A protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1784 of the SCN5A protein (p.Glu1784Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome, sick sinus syndrome, and/or Brugada syndrome (PMID: 10377081, 10727653, 10961955, 10973849, 12877697, 16379539, 18451998, 18452873, 19841300, 21321465, 23631430, 24762805). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9377). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 32533946) did not meet the statistical confidence thresholds required to predict the impact of this variant on SCN5A function. Experimental studies have shown that this missense change affects SCN5A function (PMID: 10377081, 10727653, 18451998). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 01, 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: SCV004361604.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces glutamate with lysine at codon 1784 of the SCN5A protein. This variant is found within the highly conserved C-terminal region (a.a. … (more)
This missense variant replaces glutamate with lysine at codon 1784 of the SCN5A protein. This variant is found within the highly conserved C-terminal region (a.a. 1773-2016). Rare nontruncating variants in this region have been shown to be significantly overrepresented in individuals with Brugada syndrome or Long QT syndrome (PMID: 32893267). Functional studies have shown that this variant causes a reduction in peak sodium currents, a negative shift of steady-state inactivation, and an increase in late sodium currents in transfected cells (PMID: 18451998, 24439875, 27381756). This variant has been reported in over two hundred individuals affected with Brugada syndrome, long QT syndrome, sinus node dysfunction, or cardiac conduction disease from various population (PMID: 10377081, 18451998, 20129283, 21321465, 27381756, 27566755, 33164571). This variant has been shown to segregate with disease in multiple families (PMID: 10377081, 18451998, 27381756). Some carriers have exhibited phenotypic characteristics of both Brugada syndrome and long QT syndrome (PMID: 18451998, 21321465, 27381756, 28781849). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Dec 01, 2019)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001248023.20
First in ClinVar: May 12, 2020 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 6
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Pathogenic
(Apr 26, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000610392.1
First in ClinVar: Nov 04, 2017 Last updated: Nov 04, 2017 |
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Pathogenic
(May 28, 2020)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome 3
Affected status: yes
Allele origin:
unknown
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Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues
Accession: SCV001435334.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446504.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Right bundle branch block (present) , Abnormal ST segment (present) , ST segment elevation (present)
Sex: male
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Pathogenic
(Jan 05, 2022)
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criteria provided, single submitter
Method: clinical testing
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SCN5A-Related Disorders
Affected status: yes
Allele origin:
germline
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DASA
Accession: SCV002061264.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
Comment:
The c.5350G>A;p.(Glu1784Lys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 9377; OMIM: 600163.0008; PMID: 18451998; … (more)
The c.5350G>A;p.(Glu1784Lys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 9377; OMIM: 600163.0008; PMID: 18451998; 10377081; 24762805; 10727653; 21321465; 19841300; 12877697; 10973849) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 10377081, 10727653, 18451998) - PS3_moderate. The variant is present at low allele frequencies population databases (rs137854601– gnomAD 0.0001973%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The variant co-segregated with disease in multiple affected family members (PMID: 18451998; 10377081; 24762805) - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. (less)
Number of individuals with the variant: 1
Sex: male
Geographic origin: Brazil
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Pathogenic
(Jun 18, 2021)
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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: SCV000319877.6
First in ClinVar: Oct 02, 2016 Last updated: Nov 29, 2022 |
Comment:
The p.E1784K pathogenic mutation (also known as c.5350G>A), located in coding exon 27 of the SCN5A gene, results from a G to A substitution at … (more)
The p.E1784K pathogenic mutation (also known as c.5350G>A), located in coding exon 27 of the SCN5A gene, results from a G to A substitution at nucleotide position 5350. The glutamic acid at codon 1784 is replaced by lysine, an amino acid with some similar properties. The first report of this mutation involved a family with a clinical diagnosis of autosomal dominant long QT syndrome (LQTS), in which the mutation was confirmed to co-segregrate in all affected, but none of the unaffected, family members. Functional analysis revealed a negative shift of steady-state sodium channel activation, thus suggesting delayed cardiac repolarization (Wei et al. Circulation. 1999:99(24):3165-71). Additional functional analysis revealed p.E1784K induced persistent inward sodium current activity with a faster recovery from the inactivation state suggesting an unstable inactivation state overall (Deschenes et al. Cardiovasc Res. 2000;46(1):55-65). There are reports of mixed clinical phenotypes involving LQTS, Brugada syndrome (BrS), and sinus node dysfunction among individuals with the p.E1784K mutation (Makita et al. J Clin Invest. 2008;118(6):2219-29; Sandhu A et al. Clin Case Rep 2017 Aug;5(8):1315-1319). This is considered the most common SCN5A mutation, and most recently demonstrated segregation in a family with BrS, LQTS, and cardiac conduction disease (CCD) (Veltmann C et al. J Am Heart Assoc. 2016;5(7):e003379). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Oct 26, 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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GeneDx
Accession: SCV000235527.14
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect … (more)
Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Functional studies have shown that E1784K results in SCN5A channel dysfunction by causing a persistent inward sodium current and a negative shift in steady-state inactivation (Wei et al., 1999; Deschenes et al., 2000; Makita et al., 2008; Abdelsayed et al., 2018); This variant is associated with the following publications: (PMID: 10727653, 18451998, 15840476, 31737537, 10377081, 24784157, 26131924, 21321465, 26831253, 27381756, 27677334, 28341781, 28412158, 28781849, 24871449, 10973849, 10961955, 19716085, 30364184, 29483621, 24762805, 19841300, 12877697, 16379539, 18452873, 23631430, 18508782, 30530868, 28976236, 28734073, 30662450, 31484910, 30193851, 32161207, 31447099, 32383558, 33131149) (less)
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Pathogenic
(May 26, 2015)
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no assertion criteria provided
Method: clinical testing
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Not provided
Affected status: not provided
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000280478.1
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
Comment:
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case … (more)
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Glu1784Lys (c.5350G>A) in SCN5A (NM_001099404.1, ENST00000413689) Given the very strong case data, segregation data, and absence in individuals unselected for rare cardiac disease, we consider this variant very likely disease causing and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least 30 unrelated cases of inherited channelopathy, and likely more than 52 cases (not including this patient's family). There is strong segregation data. Of note, the variant has been reported with a range of SCN5A-associated phenotypes including long QT syndrome type 3, Brugada syndrome, and conduction system disease (see Makita et al 2008 for multicenter data on the varied phenotype). Interestingly, the variant appears to be the most frequently identified long QT type 3 variant and the most frequently identified Brugada syndrome variant in a variety of cohorts. Makita et al (2008) report on 44 carriers of this variant across 15 families from multiple centers around the world (many likely overlap with prior reports). Most carriers had evidence of LQT3 (93%), 22% had evidence of Brugada syndrome, and 39% had sinus node dysfunction. All of the patients with evidence of Brugada also had evidence of long QT type 3. Half of the patients with Brugada had sinus node dysfunction. Only 2/44 carriers had no evidence of these three phenotypes, indicating high penetrance in this cohort. Of note, some carriers had evidence of all three phenotypes. Wei et al (1999) reported the variant in a Caucasian family with evidence of long QT syndrome (QTc 464-527 ms in affected relatives), sudden death at 13yo while at rest with native autopsy, sinus bradycardia, prominent unit(s) waves, ventricular ectopy during bradycardic episodes with occasional sinus pauses and one family member with "isoelectric ST segments". The authors are from Vanderbilt. They sequenced select exons of SCN5A in the family. The variant segregated with disease in 4 affected family members, including two first cousins. Priori et al (2000) reported on family with long QT syndrome and this variant. It isn't completely clear from the report, but it appears that three affected members of this family had this variant (QTc 496, 510, 520). A 12yo girl in this family had a resting QTc of 480 ms. With Flecainide provocation her QT shortened to 460 ms and ST segment elevation was provoked. Splawski et al (2000) observed the variant in 2 of 262 unrelated patients with long QT who underwent analysis of KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2. Patients were ascertained in Europe and North America (may overlap with reports by Priori's group, the US long QT registry, the international long QT registry). No ancestry, segregation, or individual phenotype data was provided. (Splawski et al 2000). Priori et al (2002) observed this variant in at least one patient with Brugada syndrome from a cohort of 130 unrelated patients with Brugada, presumably recruited in Italy (though that is not clear). Ackerman's group reported 3 unrelated patients with long QT syndrome and this variant Nemec et al 2003). They do not state where subjects were recruited, but all authors are form Mayo so presumably there. It appears that sequencing was done in Ackerman's research lab at Mayo. They note that one patient with this variant had microvoltage T wave alternans at baseline. In a subsequent paper they report an additional case, for a total of 4 (Tester et al 2005). Shim et al (2005) reported on a variant, E1783K, that appears to be the same variant, but with a slightly different number system. They observed it in two infants who underwent genetic testing at their laboratory at Boston University. Both had prolonged QT intervals and family history of sudden death in multiple family members. Behr et al (2008) identified the variant in a sudden death case from their London cohort. The variant was reported in 15 individuals in the Familion compendium, which includes 2500 patients referred for clinical long QT genetic testing (Kapplinger et al 2009). Those cases likely overlap with the data in Tester et al, Nemec et al since these are all from Ackerman's group and use data from his cohort and from the Familion cohort. Of note in considering the cases reported by Kapplinger et al (2009) is the lack of phenotypic data on this cohort, the low yield of 36% (vs. 70% in cohorts with firm diagnoses of long QT), and the lack of clarity regarding which variants were seen with another variant (9% of the cohort had multiple variants). Nakajima et al (2011) observed the variant in one of 30 Japanese probands with Brugada syndrome. Kapplinger et al (2010) reported 14 patients with this variant in their international compendium of SCN5A Brugada variants, likely overlapping with prior reports. Takahashi et al (2014) observed the variant 14 of 23 children found to have long QT syndrome through a school based ECG screening program in Okinawa, japan. There is only one submission from a clinical lab in ClinVar, Cardiovascular Biomedical Research Unit Royal Brompton & Harefield NHS Foundation Trust. They classify it as pathogenic. The variant occurs in the C terminus, just distal to the D4 transmembrane domain. Wei et al (1999) studied the effects of the variant in vitro and observed a defect in fast inactivation in xenopus oocytes. Makita et al (2008) report a negative shift in the voltage dependence of sodium channel inactivation and an increase in flecainide affinity for resting-state channels. They note these properties have been seen in other variants associated with mixed phenotypes. There is no variation at codon 1784 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~60,000 individuals of European, African, Latino and Asian descent (as of May 26th, 2015). Of note given both the patient's ancestry and the ancestry of some cases, this includes ~4300 East Asian individuals. (less)
Number of individuals with the variant: 30
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Pathogenic
(Jun 01, 2008)
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no assertion criteria provided
Method: literature only
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LONG QT SYNDROME 3
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000030193.2
First in ClinVar: Apr 04, 2013 Last updated: Nov 18, 2016 |
Comment on evidence:
Wei et al. (1999) described a family in which the 13-year-old proband died suddenly at rest with no antecedent illness and no significant findings at … (more)
Wei et al. (1999) described a family in which the 13-year-old proband died suddenly at rest with no antecedent illness and no significant findings at postmortem. Her father had sinus bradycardia with occasional sinus pauses and ventricular ectopy together with profound prolongation of his QT interval (QTc = 527 ms) (see LQT3; 603830). He experienced only occasional light-headedness. Other family members experienced occasional syncope and had sinus bradycardia and prolonged QT intervals on their ECGs. In those individuals with prolonged QT intervals, SSCP analysis detected an aberrant conformer in the coding region of the SCN5A gene corresponding to the C terminus. Nucleotide sequencing revealed a G-to-A transition at codon 1784, resulting in a glu-to-lys substitution. This mutation occurs at a highly conserved residue in most voltage-gated sodium channels in most animals, including invertebrates. When the mutation was expressed in Xenopus oocytes, a defect in channel inactivation was demonstrated in the form of a small residual steady state current throughout prolonged depolarization. Wei et al. (1999) explored this further by engineering SCN5A constructs with amino acid substitutions at other positions in the C terminus. All exhibited similar electrophysiologic phenotypes, suggesting that heterozygous charge-neutralizing amino acid substitution at this site causes an allosteric effect on sodium channel gating, resulting in delayed myocardial repolarization. This provided a novel mechanism for LQT3. Makita et al. (2008) genotyped 66 members of 44 LQT3 families of multiple ethnicities and identified the E1784K mutation in 41 individuals from 15 (34%) of the kindreds, including the family previously reported by Wei et al. (1999); the diagnoses in these individuals included LQT3 syndrome, Brugada syndrome (BRGDA1; 601144), and/or sinus node disease (see 608567). Heterologously expressed E1784K channels showed a 15.0-mV negative shift in the voltage dependence of Na channel inactivation and a 7.5-fold increase in flecainide affinity for resting-state channels, properties also seen with other LQT3 mutations associated with a mixed clinical phenotype. Furthermore, these properties were absent in Na channels harboring the T1304M mutation, which is associated with LQT3 without a mixed clinical phenotype. Makita et al. (2008) suggested that a negative shift of steady-state Na channel inactivation and enhanced tonic block by class IC drugs represent common biophysical mechanisms underlying the phenotypic overlap of LQT3 and Brugada syndromes, and further indicated that class IC drugs should be avoided in patients with Na channels displaying these behaviors. (less)
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Pathogenic
(Jun 01, 2008)
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no assertion criteria provided
Method: literature only
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BRUGADA SYNDROME 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000030194.2
First in ClinVar: Apr 04, 2013 Last updated: Nov 14, 2016 |
Comment on evidence:
Wei et al. (1999) described a family in which the 13-year-old proband died suddenly at rest with no antecedent illness and no significant findings at … (more)
Wei et al. (1999) described a family in which the 13-year-old proband died suddenly at rest with no antecedent illness and no significant findings at postmortem. Her father had sinus bradycardia with occasional sinus pauses and ventricular ectopy together with profound prolongation of his QT interval (QTc = 527 ms) (see LQT3; 603830). He experienced only occasional light-headedness. Other family members experienced occasional syncope and had sinus bradycardia and prolonged QT intervals on their ECGs. In those individuals with prolonged QT intervals, SSCP analysis detected an aberrant conformer in the coding region of the SCN5A gene corresponding to the C terminus. Nucleotide sequencing revealed a G-to-A transition at codon 1784, resulting in a glu-to-lys substitution. This mutation occurs at a highly conserved residue in most voltage-gated sodium channels in most animals, including invertebrates. When the mutation was expressed in Xenopus oocytes, a defect in channel inactivation was demonstrated in the form of a small residual steady state current throughout prolonged depolarization. Wei et al. (1999) explored this further by engineering SCN5A constructs with amino acid substitutions at other positions in the C terminus. All exhibited similar electrophysiologic phenotypes, suggesting that heterozygous charge-neutralizing amino acid substitution at this site causes an allosteric effect on sodium channel gating, resulting in delayed myocardial repolarization. This provided a novel mechanism for LQT3. Makita et al. (2008) genotyped 66 members of 44 LQT3 families of multiple ethnicities and identified the E1784K mutation in 41 individuals from 15 (34%) of the kindreds, including the family previously reported by Wei et al. (1999); the diagnoses in these individuals included LQT3 syndrome, Brugada syndrome (BRGDA1; 601144), and/or sinus node disease (see 608567). Heterologously expressed E1784K channels showed a 15.0-mV negative shift in the voltage dependence of Na channel inactivation and a 7.5-fold increase in flecainide affinity for resting-state channels, properties also seen with other LQT3 mutations associated with a mixed clinical phenotype. Furthermore, these properties were absent in Na channels harboring the T1304M mutation, which is associated with LQT3 without a mixed clinical phenotype. Makita et al. (2008) suggested that a negative shift of steady-state Na channel inactivation and enhanced tonic block by class IC drugs represent common biophysical mechanisms underlying the phenotypic overlap of LQT3 and Brugada syndromes, and further indicated that class IC drugs should be avoided in patients with Na channels displaying these behaviors. (less)
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Pathogenic
(Jun 01, 2008)
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no assertion criteria provided
Method: literature only
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SINUS NODE DISEASE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000030195.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 11, 2015 |
Comment on evidence:
Wei et al. (1999) described a family in which the 13-year-old proband died suddenly at rest with no antecedent illness and no significant findings at … (more)
Wei et al. (1999) described a family in which the 13-year-old proband died suddenly at rest with no antecedent illness and no significant findings at postmortem. Her father had sinus bradycardia with occasional sinus pauses and ventricular ectopy together with profound prolongation of his QT interval (QTc = 527 ms) (see LQT3; 603830). He experienced only occasional light-headedness. Other family members experienced occasional syncope and had sinus bradycardia and prolonged QT intervals on their ECGs. In those individuals with prolonged QT intervals, SSCP analysis detected an aberrant conformer in the coding region of the SCN5A gene corresponding to the C terminus. Nucleotide sequencing revealed a G-to-A transition at codon 1784, resulting in a glu-to-lys substitution. This mutation occurs at a highly conserved residue in most voltage-gated sodium channels in most animals, including invertebrates. When the mutation was expressed in Xenopus oocytes, a defect in channel inactivation was demonstrated in the form of a small residual steady state current throughout prolonged depolarization. Wei et al. (1999) explored this further by engineering SCN5A constructs with amino acid substitutions at other positions in the C terminus. All exhibited similar electrophysiologic phenotypes, suggesting that heterozygous charge-neutralizing amino acid substitution at this site causes an allosteric effect on sodium channel gating, resulting in delayed myocardial repolarization. This provided a novel mechanism for LQT3. Makita et al. (2008) genotyped 66 members of 44 LQT3 families of multiple ethnicities and identified the E1784K mutation in 41 individuals from 15 (34%) of the kindreds, including the family previously reported by Wei et al. (1999); the diagnoses in these individuals included LQT3 syndrome, Brugada syndrome (BRGDA1; 601144), and/or sinus node disease (see 608567). Heterologously expressed E1784K channels showed a 15.0-mV negative shift in the voltage dependence of Na channel inactivation and a 7.5-fold increase in flecainide affinity for resting-state channels, properties also seen with other LQT3 mutations associated with a mixed clinical phenotype. Furthermore, these properties were absent in Na channels harboring the T1304M mutation, which is associated with LQT3 without a mixed clinical phenotype. Makita et al. (2008) suggested that a negative shift of steady-state Na channel inactivation and enhanced tonic block by class IC drugs represent common biophysical mechanisms underlying the phenotypic overlap of LQT3 and Brugada syndromes, and further indicated that class IC drugs should be avoided in patients with Na channels displaying these behaviors. (less)
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Pathogenic
(Feb 25, 2016)
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no assertion criteria provided
Method: research
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Long QT syndrome 3
Affected status: yes
Allele origin:
germline
|
Division of Human Genetics, Children's Hospital of Philadelphia
Study: CSER-PediSeq
Accession: SCV000536870.1 First in ClinVar: Nov 18, 2016 Last updated: Nov 18, 2016 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001924000.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001742855.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001952109.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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Congenital long QT syndrome
Affected status: unknown
Allele origin:
germline
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Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust
Accession: SCV000090293.3
First in ClinVar: Oct 22, 2013 Last updated: Oct 09, 2016 |
Comment:
This variant has been reported as associated with Long QT syndrome in the following publications (PMID:10377081;PMID:10961955;PMID:10973849;PMID:12877697;PMID:15840476;PMID:16379539;PMID:18451998;PMID:19716085;PMID:19841300;PMID:10727653). This is a literature report, and does not necessarily … (more)
This variant has been reported as associated with Long QT syndrome in the following publications (PMID:10377081;PMID:10961955;PMID:10973849;PMID:12877697;PMID:15840476;PMID:16379539;PMID:18451998;PMID:19716085;PMID:19841300;PMID:10727653). 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 |
---|---|---|---|---|
Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls. | Walsh R | Genetics in medicine : official journal of the American College of Medical Genetics | 2021 | PMID: 32893267 |
SCN5A Mutation Type and a Genetic Risk Score Associate Variably With Brugada Syndrome Phenotype in SCN5A Families. | Wijeyeratne YD | Circulation. Genomic and precision medicine | 2020 | PMID: 33164571 |
High-Throughput Reclassification of SCN5A Variants. | Glazer AM | American journal of human genetics | 2020 | PMID: 32533946 |
KIF1A-related disorders in children: A wide spectrum of central and peripheral nervous system involvement. | Nemani T | Journal of the peripheral nervous system : JPNS | 2020 | PMID: 32096284 |
Variant panorama in 1,385 index patients and sensitivity of expanded next-generation sequencing panels in arrhythmogenic disorders. | Marschall C | Cardiovascular diagnosis and therapy | 2019 | PMID: 31737537 |
Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network. | eMERGE Consortium. Electronic address: agibbs@bcm.edu | American journal of human genetics | 2019 | PMID: 31447099 |
PEHO syndrome: KIF1A mutation and decreased activity of mitochondrial respiratory chain complex. | Samanta D | Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia | 2019 | PMID: 30385166 |
Dysfunctional Nav1.5 channels due to SCN5A mutations. | Han D | Experimental biology and medicine (Maywood, N.J.) | 2018 | PMID: 29806494 |
Double jeopardy: long QT3 and Brugada syndromes. | Sandhu A | Clinical case reports | 2017 | PMID: 28781849 |
Clinical Aspects of Type 3 Long-QT Syndrome: An International Multicenter Study. | Wilde AA | Circulation | 2016 | PMID: 27566755 |
Further Insights in the Most Common SCN5A Mutation Causing Overlapping Phenotype of Long QT Syndrome, Brugada Syndrome, and Conduction Defect. | Veltmann C | Journal of the American Heart Association | 2016 | PMID: 27381756 |
De novo mutations in KIF1A cause progressive encephalopathy and brain atrophy. | Esmaeeli Nieh S | Annals of clinical and translational neurology | 2015 | PMID: 26125038 |
The implications of familial incidental findings from exome sequencing: the NIH Undiagnosed Diseases Program experience. | Lawrence L | Genetics in medicine : official journal of the American College of Medical Genetics | 2014 | PMID: 24784157 |
Sodium channelopathy underlying familial sick sinus syndrome with early onset and predominantly male characteristics. | Abe K | Circulation. Arrhythmia and electrophysiology | 2014 | PMID: 24762805 |
ABCC9 is a novel Brugada and early repolarization syndrome susceptibility gene. | Hu D | International journal of cardiology | 2014 | PMID: 24439875 |
Results of genetic testing in 855 consecutive unrelated patients referred for long QT syndrome in a clinical laboratory. | Lieve KV | Genetic testing and molecular biomarkers | 2013 | PMID: 23631430 |
Identification of six novel SCN5A mutations in Japanese patients with Brugada syndrome. | Nakajima T | International heart journal | 2011 | PMID: 21321465 |
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 |
Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants. | Kapa S | Circulation | 2009 | PMID: 19841300 |
Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test. | Kapplinger JD | Heart rhythm | 2009 | PMID: 19716085 |
Sudden arrhythmic death syndrome: familial evaluation identifies inheritable heart disease in the majority of families. | Behr ER | European heart journal | 2008 | PMID: 18508782 |
Prevalence of early-onset atrial fibrillation in congenital long QT syndrome. | Johnson JN | Heart rhythm | 2008 | PMID: 18452873 |
The E1784K mutation in SCN5A is associated with mixed clinical phenotype of type 3 long QT syndrome. | Makita N | The Journal of clinical investigation | 2008 | PMID: 18451998 |
Gene sequencing in neonates and infants with the long QT syndrome. | Shim SH | Genetic testing | 2005 | PMID: 16379539 |
Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing. | Tester DJ | Heart rhythm | 2005 | PMID: 15840476 |
Catecholamine-provoked microvoltage T wave alternans in genotyped long QT syndrome. | Nemec J | Pacing and clinical electrophysiology : PACE | 2003 | PMID: 12877697 |
Natural history of Brugada syndrome: insights for risk stratification and management. | Priori SG | Circulation | 2002 | PMID: 11901046 |
Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. | Splawski I | Circulation | 2000 | PMID: 10973849 |
The elusive link between LQT3 and Brugada syndrome: the role of flecainide challenge. | Priori SG | Circulation | 2000 | PMID: 10961955 |
Electrophysiological characterization of SCN5A mutations causing long QT (E1784K) and Brugada (R1512W and R1432G) syndromes. | Deschênes I | Cardiovascular research | 2000 | PMID: 10727653 |
Congenital long-QT syndrome caused by a novel mutation in a conserved acidic domain of the cardiac Na+ channel. | Wei J | Circulation | 1999 | PMID: 10377081 |
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Text-mined citations for rs137854601 ...
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.