ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.3266C>T (p.Pro1089Leu)
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
-
NM_000335.5(SCN5A):c.3266C>T (p.Pro1089Leu)
Variation ID: 48298 Accession: VCV000048298.35
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 38579455 (GRCh38) [ NCBI UCSC ] 3: 38620946 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 4, 2015 May 1, 2024 Jan 27, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000335.5:c.3266C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000326.2:p.Pro1089Leu missense NM_001099404.2:c.3269C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001092874.1:p.Pro1090Leu missense NM_001099405.2:c.3269C>T NP_001092875.1:p.Pro1090Leu missense NM_001160160.2:c.3266C>T NP_001153632.1:p.Pro1089Leu missense NM_001160161.2:c.3228+1476C>T intron variant NM_001354701.2:c.3266C>T NP_001341630.1:p.Pro1089Leu missense NM_198056.3:c.3269C>T NP_932173.1:p.Pro1090Leu missense NC_000003.12:g.38579455G>A NC_000003.11:g.38620946G>A NG_008934.1:g.75218C>T NG_053884.1:g.1194G>A LRG_289:g.75218C>T LRG_289t1:c.3269C>T LRG_289p1:p.Pro1090Leu Q14524:p.Pro1090Leu - Protein change
- P1089L, P1090L
- Other names
- p.P1090L:CCG>CTG
- Canonical SPDI
- NC_000003.12:38579454: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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0.00439 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD) 0.00071
Trans-Omics for Precision Medicine (TOPMed) 0.00118
Exome Aggregation Consortium (ExAC) 0.00171
1000 Genomes Project 30x 0.00406
1000 Genomes Project 0.00439
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
Help
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 |
3739 | 4175 | |
LOC110121269 | - | - | - | GRCh38 | - | 417 |
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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Benign/Likely benign (6) |
criteria provided, multiple submitters, no conflicts
|
Jun 24, 2013 | RCV000041614.21 | |
Benign/Likely benign (5) |
criteria provided, multiple submitters, no conflicts
|
Jan 27, 2024 | RCV000058559.21 | |
Benign (1) |
criteria provided, single submitter
|
Mar 25, 2015 | RCV000242258.11 | |
Likely benign (1) |
criteria provided, single submitter
|
May 8, 2018 | RCV000852963.9 | |
Benign (1) |
criteria provided, multiple submitters, no conflicts
|
May 17, 2019 | RCV001084763.13 | |
Likely benign (1) |
criteria provided, single submitter
|
May 9, 2018 | RCV001149369.12 | |
Benign (1) |
criteria provided, single submitter
|
May 9, 2018 | RCV001149371.12 | |
Likely benign (1) |
criteria provided, single submitter
|
May 9, 2018 | RCV001149367.12 | |
Likely benign (1) |
criteria provided, single submitter
|
May 9, 2018 | RCV001149372.12 | |
Likely benign (1) |
criteria provided, single submitter
|
May 9, 2018 | RCV001149368.12 | |
Likely benign (1) |
criteria provided, single submitter
|
May 9, 2018 | RCV001149370.12 | |
Likely benign (1) |
criteria provided, single submitter
|
May 31, 2022 | RCV002483030.8 | |
Benign (1) |
criteria provided, single submitter
|
Mar 19, 2018 | RCV001841602.10 | |
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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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Benign
(Jun 24, 2013)
|
criteria provided, single submitter
Method: research
|
not specified
Affected status: unknown
Allele origin:
unknown
|
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Study: ClinSeq
Accession: SCV000050839.1 First in ClinVar: Jun 04, 2015 Last updated: Jun 04, 2015
Comments (2):
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:23861362 for … (more)
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:23861362 for details. (less)
Medical sequencing
|
Number of individuals with the variant: 1
|
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Likely benign
(May 09, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Ventricular fibrillation, paroxysmal familial, type 1
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001310316.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
|
|
Likely benign
(May 09, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Progressive familial heart block, type 1A
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001310321.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
|
|
Likely benign
(May 09, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Long QT syndrome 3
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001310317.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
|
|
Likely benign
(May 09, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Brugada syndrome 1
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001310318.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
|
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Likely benign
(May 09, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Dilated cardiomyopathy 1E
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001310319.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
|
|
Benign
(May 09, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Sick sinus syndrome 1
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001310320.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. (less)
|
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Likely benign
(May 31, 2022)
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criteria provided, single submitter
Method: clinical testing
|
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
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002797349.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
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Benign
(Mar 19, 2018)
|
criteria provided, single submitter
Method: clinical testing
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Arrhythmia
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000902961.1
First in ClinVar: May 20, 2019 Last updated: May 20, 2019 |
|
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Likely benign
(Nov 05, 2012)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000065310.6
First in ClinVar: May 03, 2013 Last updated: May 03, 2018 |
Comment:
Pro1090Leu in exon 18 of SCN5A: This variant is not expected to have clinical si gnificance because it has been identified in 2.1% (12/572) of … (more)
Pro1090Leu in exon 18 of SCN5A: This variant is not expected to have clinical si gnificance because it has been identified in 2.1% (12/572) of chromosomes from a broad, though clinically and racially unspecified population from 1000 Genomes Project (http://1000genomes.org; rs1805125). Pro1090Leu in exon 18 of SCN5A (r s1805125; allele frequency = 2.1%, 12/572) (less)
Number of individuals with the variant: 3
|
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Likely benign
(May 08, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy
Affected status: yes
Allele origin:
germline
|
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego
Accession: SCV000995712.1
First in ClinVar: Oct 12, 2019 Last updated: Oct 12, 2019 |
Number of individuals with the variant: 1
|
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Benign
(Jan 27, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000291798.9
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
|
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Benign
(Nov 30, 2011)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000171566.10
First in ClinVar: Jun 23, 2014 Last updated: Jul 05, 2015 |
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more)
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
|
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Benign
(May 17, 2019)
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criteria provided, single submitter
Method: clinical testing
|
Brugada syndrome
Affected status: yes
Allele origin:
germline
|
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals
Accession: SCV001338813.1
First in ClinVar: Jun 18, 2020 Last updated: Jun 18, 2020 |
|
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Likely benign
(Nov 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV004563062.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
|
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Benign
(Jul 01, 2023)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004033983.5
First in ClinVar: Sep 16, 2023 Last updated: Apr 15, 2024 |
Comment:
SCN5A: PP3, BS1, BS2
Number of individuals with the variant: 1
|
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Benign
(Mar 25, 2015)
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criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000318823.7
First in ClinVar: Oct 02, 2016 Last updated: May 01, 2024 |
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more)
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001920603.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
|
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Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001928174.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
|
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Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
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: SCV001953296.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001974458.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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not provided
(-)
|
no classification provided
Method: literature only
|
not provided
Affected status: unknown
Allele origin:
germline
|
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust
Accession: SCV000090079.3
First in ClinVar: Oct 22, 2013 Last updated: Oct 09, 2016 |
Comment:
This variant has been reported in the following publications (PMID:10807545;PMID:15689442;PMID:16155735;PMID:18426444;PMID:19841300;PMID:20129283).
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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 |
---|---|---|---|---|
Utilizing multiple in silico analyses to identify putative causal SCN5A variants in Brugada syndrome. | Juang JM | Scientific reports | 2014 | PMID: 24463578 |
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 |
Single nucleotide polymorphisms and haplotype of four genes encoding cardiac ion channels in Chinese and their association with arrhythmia. | Zhang Y | Annals of noninvasive electrocardiology : the official journal of the International Society for Holter and Noninvasive Electrocardiology, Inc | 2008 | PMID: 18426444 |
Non-SCN5A related Brugada syndromes: verification of normal splicing and trafficking of SCN5A without exonic mutations. | Nakano Y | Annals of human genetics | 2007 | PMID: 17227473 |
Denaturing high-performance liquid chromatography screening of the long QT syndrome-related cardiac sodium and potassium channel genes and identification of novel mutations and single nucleotide polymorphisms. | Lai LP | Journal of human genetics | 2005 | PMID: 16155735 |
R1193Q of SCN5A, a Brugada and long QT mutation, is a common polymorphism in Han Chinese. | Hwang HW | Journal of medical genetics | 2005 | PMID: 15689442 |
Spectrum and prevalence of cardiac sodium channel variants among black, white, Asian, and Hispanic individuals: implications for arrhythmogenic susceptibility and Brugada/long QT syndrome genetic testing. | Ackerman MJ | Heart rhythm | 2004 | PMID: 15851227 |
Twenty single nucleotide polymorphisms (SNPs) and their allelic frequencies in four genes that are responsible for familial long QT syndrome in the Japanese population. | Iwasa H | Journal of human genetics | 2000 | PMID: 10807545 |
Text-mined citations for rs1805125 ...
HelpRecord last updated May 08, 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.