ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.3575G>A (p.Arg1192Gln)
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.3575G>A (p.Arg1192Gln)
Variation ID: 9392 Accession: VCV000009392.38
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3p22.2 3: 38575385 (GRCh38) [ NCBI UCSC ] 3: 38616876 (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 Feb 6, 2015 Sep 29, 2024 Feb 1, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000335.5:c.3575G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000326.2:p.Arg1192Gln missense NM_001099404.2:c.3578G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001092874.1:p.Arg1193Gln missense NM_001099405.2:c.3578G>A NP_001092875.1:p.Arg1193Gln missense NM_001160160.2:c.3575G>A NP_001153632.1:p.Arg1192Gln missense NM_001160161.2:c.3416G>A NP_001153633.1:p.Arg1139Gln missense NM_001354701.2:c.3575G>A NP_001341630.1:p.Arg1192Gln missense NM_198056.3:c.3578G>A NP_932173.1:p.Arg1193Gln missense NC_000003.12:g.38575385C>T NC_000003.11:g.38616876C>T NG_008934.1:g.79288G>A LRG_289:g.79288G>A LRG_289t1:c.3578G>A LRG_289p1:p.Arg1193Gln LRG_289t2:c.3575G>A LRG_289p2:p.Arg1192Gln LRG_289t3:c.3578G>A LRG_289p3:p.Arg1193Gln - Protein change
- R1193Q, R1192Q, R1139Q
- Other names
- p.R1193Q:CGG>CAG
- Canonical SPDI
- NC_000003.12:38575384: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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0.01238 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 0.01238
The Genome Aggregation Database (gnomAD) 0.00222
Trans-Omics for Precision Medicine (TOPMed) 0.00303
The Genome Aggregation Database (gnomAD), exomes 0.00535
Exome Aggregation Consortium (ExAC) 0.00622
1000 Genomes Project 30x 0.01156
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 |
3779 | 4220 |
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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risk factor (1) |
no assertion criteria provided
|
Oct 1, 2006 | RCV000009991.12 | |
Benign (2) |
criteria provided, single submitter
|
Mar 6, 2018 | RCV000009990.17 | |
Benign/Likely benign (6) |
criteria provided, multiple submitters, no conflicts
|
Feb 1, 2024 | RCV000058578.28 | |
Benign/Likely benign (3) |
criteria provided, multiple submitters, no conflicts
|
Dec 28, 2016 | RCV000154828.19 | |
Uncertain significance (1) |
no assertion criteria provided
|
Apr 17, 2014 | RCV000157488.9 | |
Benign (1) |
criteria provided, single submitter
|
Jun 24, 2013 | RCV000171819.21 | |
Benign (1) |
criteria provided, single submitter
|
Feb 1, 2016 | RCV000252422.11 | |
Benign (2) |
criteria provided, multiple submitters, no conflicts
|
Nov 21, 2018 | RCV000755697.14 | |
Benign (1) |
criteria provided, single submitter
|
Mar 6, 2018 | RCV001147625.12 | |
Likely benign (1) |
criteria provided, single submitter
|
Mar 6, 2018 | RCV001147624.12 | |
Benign (1) |
criteria provided, single submitter
|
Mar 6, 2018 | RCV001147626.12 | |
Likely benign (1) |
criteria provided, single submitter
|
Mar 6, 2018 | RCV001147627.12 | |
Benign (1) |
criteria provided, single submitter
|
Mar 15, 2018 | RCV001841238.10 | |
Benign (1) |
criteria provided, single submitter
|
Oct 21, 2021 | RCV002476954.8 | |
Benign (1) |
criteria provided, single submitter
|
Sep 15, 2021 | RCV003149566.9 | |
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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
(Nov 21, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Long QT syndrome 3
Affected status: unknown
Allele origin:
unknown
|
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV000883129.1
First in ClinVar: Feb 18, 2019 Last updated: Feb 18, 2019 |
|
|
Benign
(Mar 30, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001472663.3
First in ClinVar: Jan 26, 2021 Last updated: Mar 04, 2023 |
|
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Benign
(Apr 29, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000171568.5
First in ClinVar: Jun 23, 2014 Last updated: Mar 04, 2023 |
Comment:
This variant is associated with the following publications: (PMID: 23465283, 22378279, 22995991, 24784157, 20129283, 15851227, 15992732, 18976777, 23853484, 15121794, 15689442, 22682427, 25051102, 20981092, 22519808, 17605181, … (more)
This variant is associated with the following publications: (PMID: 23465283, 22378279, 22995991, 24784157, 20129283, 15851227, 15992732, 18976777, 23853484, 15121794, 15689442, 22682427, 25051102, 20981092, 22519808, 17605181, 11823453, 26131924, 26159999, 27153395, 15851440, 16568155, 28472724, 28493952, 29672598, 29997009, 28498465, 30419068, 30079003, 31019283, 30677491, 31043699, 31539150, 31751991, 31918855, 28878402, 18245395, 33131149) (less)
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Benign
(Jun 24, 2013)
|
criteria provided, single submitter
Method: research
|
Sudden unexplained nocturnal death syndrome
Affected status: unknown
Allele origin:
unknown
|
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Study: ClinSeq
Accession: SCV000050843.1 First in ClinVar: Jun 08, 2015 Last updated: Jun 08, 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: 5
|
|
Benign
(-)
|
criteria provided, single submitter
Method: clinical testing
|
NOT SPECIFIED
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV000306543.1
First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016 |
|
|
Likely benign
(Dec 28, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000748020.1
First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016 |
|
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Benign
(Mar 15, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Arrhythmia
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000910629.1
First in ClinVar: May 20, 2019 Last updated: May 20, 2019 |
|
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Benign
(Oct 18, 2013)
|
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: SCV000204510.5
First in ClinVar: Jan 31, 2015 Last updated: Oct 02, 2016 |
Comment:
Arg1193Gln in exon 20 of SCN5A: This variant is not expected to have clinical si gnificance because it has been identified in 5.1% (20/394) Chinese … (more)
Arg1193Gln in exon 20 of SCN5A: This variant is not expected to have clinical si gnificance because it has been identified in 5.1% (20/394) Chinese chromosomes b y the 1000 Genomes Project (dbSNP rs41261344). (less)
Number of individuals with the variant: 7
|
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Likely benign
(Dec 03, 2018)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics
Accession: SCV001145504.1
First in ClinVar: Jan 19, 2020 Last updated: Jan 19, 2020 |
|
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Benign
(Mar 06, 2018)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome 3
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001308460.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
|
|
Likely benign
(Mar 06, 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: SCV001308461.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less)
|
|
Benign
(Mar 06, 2018)
|
criteria provided, single submitter
Method: clinical testing
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Sick sinus syndrome 1
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001308462.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
|
|
Benign
(Mar 06, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Brugada syndrome 1
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000443977.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
|
|
Likely benign
(Mar 06, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Dilated cardiomyopathy 1E
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001308464.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less)
|
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Benign
(Mar 06, 2018)
|
criteria provided, single submitter
Method: clinical testing
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Ventricular fibrillation, paroxysmal familial, type 1
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001308463.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
|
|
Benign
(Oct 21, 2021)
|
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: SCV002797841.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
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Benign
(Sep 15, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV003838880.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
|
|
Benign
(Feb 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000262483.10
First in ClinVar: Jan 31, 2016 Last updated: Feb 20, 2024 |
|
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Benign
(Feb 01, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000318184.7
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)
|
|
Likely benign
(-)
|
criteria provided, single submitter
Method: not provided
|
not provided
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Breakthrough Genomics, Breakthrough Genomics
Accession: SCV005258477.1
First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024 |
|
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Pathogenic
(Oct 01, 2006)
|
no assertion criteria provided
Method: literature only
|
BRUGADA SYNDROME 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000030211.4
First in ClinVar: Apr 04, 2013 Last updated: Jan 20, 2017 |
Comment on evidence:
In a pair of Japanese dizygotic twins, one of whom died at 4 months of SUNDS, a disorder identical to Brugada syndrome (BRGDA1; 601144), Vatta … (more)
In a pair of Japanese dizygotic twins, one of whom died at 4 months of SUNDS, a disorder identical to Brugada syndrome (BRGDA1; 601144), Vatta et al. (2002) identified a 3575G-A transition in exon 20 of the SCN5A gene, predicted to result in an arg1192-to-gln (R1192Q) substitution in Domain III. In transfected Xenopus oocytes, the mutation accelerated the inactivation of the sodium channel current and exhibited reduced sodium channel current at the end of phase I of the action potential. Wang (2005) stated that this variant was mislabeled in the Vatta et al. (2002) report and should be designated R1993Q. In an 82-year-old Caucasian male who developed long QT syndrome after the administration of D-sotolol or quinidine (see LQT3, 603830), Wang et al. (2004) identified heterozygosity for the R1993Q mutation in the SCN5A gene. The mutation was found in 4 of 2,087 predominantly Caucasian controls (0.2%). Electrophysiologic studies showed that mutant R1193Q channels destabilize inactivation gating and generate a persistent, nonactivating current that is expected to prolong the cardiac action potential duration, leading to LQT syndrome; single channel recording revealed the molecular mechanism to be frequent, dispersed reopening of the channels. The patient also carried the H558R SCN5A variant (600163.0031), but due to a lack of family members, it could not be determined whether H558R was in cis or trans with R1993Q. Hwang et al. (2005) found the R1993Q mutation in 11 of 94 (12%) randomly selected Han Chinese individuals and concluded that the variant is a common polymorphism in this population. None of the carriers had electrocardiographic signs of Brugada syndrome, although 1 had a prolonged QTc interval (472 ms) and another, who was homozygous for the mutation, had a borderline long QTc (437 ms). In an asymptomatic 73-year-old male member of a 4-generation Han Chinese family with autosomal dominant cardiac arrhythmias and sudden death, Niu et al. (2006) identified compound heterozygosity for R1193Q and a nonsense mutation in the SCN5A gene (W1421X; 600163.0036). Niu et al. (2006) suggested that the R1193Q mutation, which results in a gain of sodium channel function, may compensate for the deleterious effects of W1421X. Haplotype analysis of an asymptomatic daughter-in-law and 2 asymptomatic grandchildren who also carried the R1193Q mutation revealed that the children inherited the mutation from their mother rather than their grandfather. (less)
|
|
risk factor
(Oct 01, 2006)
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no assertion criteria provided
Method: literature only
|
LONG QT SYNDROME 3, ACQUIRED, SUSCEPTIBILITY TO
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000030212.4
First in ClinVar: Apr 04, 2013 Last updated: Nov 14, 2016 |
Comment on evidence:
In a pair of Japanese dizygotic twins, one of whom died at 4 months of SUNDS, a disorder identical to Brugada syndrome (BRGDA1; 601144), Vatta … (more)
In a pair of Japanese dizygotic twins, one of whom died at 4 months of SUNDS, a disorder identical to Brugada syndrome (BRGDA1; 601144), Vatta et al. (2002) identified a 3575G-A transition in exon 20 of the SCN5A gene, predicted to result in an arg1192-to-gln (R1192Q) substitution in Domain III. In transfected Xenopus oocytes, the mutation accelerated the inactivation of the sodium channel current and exhibited reduced sodium channel current at the end of phase I of the action potential. Wang (2005) stated that this variant was mislabeled in the Vatta et al. (2002) report and should be designated R1993Q. In an 82-year-old Caucasian male who developed long QT syndrome after the administration of D-sotolol or quinidine (see LQT3, 603830), Wang et al. (2004) identified heterozygosity for the R1993Q mutation in the SCN5A gene. The mutation was found in 4 of 2,087 predominantly Caucasian controls (0.2%). Electrophysiologic studies showed that mutant R1193Q channels destabilize inactivation gating and generate a persistent, nonactivating current that is expected to prolong the cardiac action potential duration, leading to LQT syndrome; single channel recording revealed the molecular mechanism to be frequent, dispersed reopening of the channels. The patient also carried the H558R SCN5A variant (600163.0031), but due to a lack of family members, it could not be determined whether H558R was in cis or trans with R1993Q. Hwang et al. (2005) found the R1993Q mutation in 11 of 94 (12%) randomly selected Han Chinese individuals and concluded that the variant is a common polymorphism in this population. None of the carriers had electrocardiographic signs of Brugada syndrome, although 1 had a prolonged QTc interval (472 ms) and another, who was homozygous for the mutation, had a borderline long QTc (437 ms). In an asymptomatic 73-year-old male member of a 4-generation Han Chinese family with autosomal dominant cardiac arrhythmias and sudden death, Niu et al. (2006) identified compound heterozygosity for R1193Q and a nonsense mutation in the SCN5A gene (W1421X; 600163.0036). Niu et al. (2006) suggested that the R1193Q mutation, which results in a gain of sodium channel function, may compensate for the deleterious effects of W1421X. Haplotype analysis of an asymptomatic daughter-in-law and 2 asymptomatic grandchildren who also carried the R1193Q mutation revealed that the children inherited the mutation from their mother rather than their grandfather. (less)
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Uncertain significance
(Apr 17, 2014)
|
no assertion criteria provided
Method: clinical testing
|
Primary familial hypertrophic cardiomyopathy
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV000207233.1
First in ClinVar: Feb 06, 2015 Last updated: Feb 06, 2015 |
Number of individuals with the variant: 1
|
|
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: SCV000090098.3
First in ClinVar: Oct 22, 2013 Last updated: Oct 09, 2016 |
Comment:
This variant has been reported in the following publications (PMID:11823453;PMID:12639704;PMID:15121794;PMID:15689442;PMID:15851227;PMID:16155735;PMID:16707561;PMID:17210839;PMID:17905336;PMID:18245395;PMID:18976777;PMID:19841300;PMID:17605181;PMID:20981092;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 |
---|---|---|---|---|
Lack of modulatory effect of the SCN5A R1193Q polymorphism on cardiac fast Na+ current at body temperature. | Abe M | PloS one | 2018 | PMID: 30419068 |
Channelopathy as a SUDEP Biomarker in Dravet Syndrome Patient-Derived Cardiac Myocytes. | Frasier CR | Stem cell reports | 2018 | PMID: 30146492 |
Retrospective Genetic Analysis of 200 Cases of Sudden Infant Death Syndrome and Its Relationship with Long QT Syndrome in Korea. | Son MJ | Journal of Korean medical science | 2018 | PMID: 30079003 |
A novel three base-pair deletion in domain two of the cardiac sodium channel causes Brugada syndrome. | Tan BY | Journal of electrocardiology | 2018 | PMID: 29997009 |
Long QT molecular autopsy in sudden unexplained death in the young (1-40 years old): Lessons learnt from an eight year experience in New Zealand. | Marcondes L | PloS one | 2018 | PMID: 29672598 |
Prenatal Diagnosis of Atrioventricular Block and QT Interval Prolongation by Fetal Magnetocardiography in a Fetus with Trisomy 18 and SCN5A R1193Q Variant. | Lin L | Case reports in pediatrics | 2017 | PMID: 28638671 |
Identification of a novel hypertrophic cardiomyopathy-associated mutation using targeted next-generation sequencing. | Zhao Y | International journal of molecular medicine | 2017 | PMID: 28498465 |
A mutation in the CACNA1C gene leads to early repolarization syndrome with incomplete penetrance: A Chinese family study. | Liu X | PloS one | 2017 | PMID: 28493952 |
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. | Nykamp K | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 28492532 |
Atrial fibrillation associated with Wolff-Parkinson-White syndrome in a patient with concomitant Brugada syndrome. | Shi S | HeartRhythm case reports | 2017 | PMID: 28491758 |
Relevance of molecular testing in patients with a family history of sudden death. | Kauferstein S | Forensic science international | 2017 | PMID: 28472724 |
Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer. | Maxwell KN | American journal of human genetics | 2016 | PMID: 27153395 |
Rare genetic variants previously associated with congenital forms of long QT syndrome have little or no effect on the QT interval. | Ghouse J | European heart journal | 2015 | PMID: 26159999 |
Differential thermosensitivity in mixed syndrome cardiac sodium channel mutants. | Abdelsayed M | The Journal of physiology | 2015 | PMID: 26131924 |
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
SCN5A mutations and polymorphisms in patients with ventricular fibrillation during acute myocardial infarction. | Boehringer T | Molecular medicine reports | 2014 | PMID: 25051102 |
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 |
Genetic mutation in Korean patients of sudden cardiac arrest as a surrogating marker of idiopathic ventricular arrhythmia. | Son MK | Journal of Korean medical science | 2013 | PMID: 23853484 |
Mutations in genes encoding cardiac ion channels previously associated with sudden infant death syndrome (SIDS) are present with high frequency in new exome data. | Andreasen C | The Canadian journal of cardiology | 2013 | PMID: 23465283 |
An autopsy case of sudden unexpected nocturnal death syndrome with R1193Q polymorphism in the SCN5A gene. | Matsusue A | Legal medicine (Tokyo, Japan) | 2012 | PMID: 22682427 |
Long QT syndrome and dilated cardiomyopathy with SCN5A p.R1193Q polymorphism: cardioverter-defibrillator implantation at 27 months. | Kwon HW | Pacing and clinical electrophysiology : PACE | 2012 | PMID: 22519808 |
High prevalence of genetic variants previously associated with LQT syndrome in new exome data. | Refsgaard L | European journal of human genetics : EJHG | 2012 | PMID: 22378279 |
A map of human genome variation from population-scale sequencing. | 1000 Genomes Project Consortium | Nature | 2010 | PMID: 20981092 |
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 |
Patient with obstructive sleep apnea-hypopnea syndrome and SCN5A mutation (R1193Q polymorphism) associated with Brugada type 2 electrocardiographic pattern. | Qiu X | Journal of electrocardiology | 2009 | PMID: 18976777 |
Cardiac sodium channel (SCN5A) variants associated with atrial fibrillation. | Darbar D | Circulation | 2008 | PMID: 18378609 |
SCN5A R1193Q polymorphism associated with progressive cardiac conduction defects and long QT syndrome in a Chinese family. | Sun A | Journal of medical genetics | 2008 | PMID: 18245395 |
Long QT and Brugada syndrome gene mutations in New Zealand. | Chung SK | Heart rhythm | 2007 | PMID: 17905336 |
[The clinical variability of and approaches to treatment of life-threatening ventricular arrhythmias caused by SCN5A gene mutations]. | Bokeria LA | Vestnik Rossiiskoi akademii meditsinskikh nauk | 2007 | PMID: 17605181 |
Prevalence of long-QT syndrome gene variants in sudden infant death syndrome. | Arnestad M | Circulation | 2007 | PMID: 17210839 |
A common SCN5A polymorphism attenuates a severe cardiac phenotype caused by a nonsense SCN5A mutation in a Chinese family with an inherited cardiac conduction defect. | Niu DM | Journal of medical genetics | 2006 | PMID: 16707561 |
Nav1.5/R1193Q polymorphism is associated with both long QT and Brugada syndromes. | Huang H | The Canadian journal of cardiology | 2006 | PMID: 16568155 |
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 |
Common human SCN5A polymorphisms have altered electrophysiology when expressed in Q1077 splice variants. | Tan BH | Heart rhythm | 2005 | PMID: 15992732 |
Near-miss SIDS due to Brugada syndrome. | Skinner JR | Archives of disease in childhood | 2005 | PMID: 15851440 |
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 |
The common SCN5A mutation R1193Q causes LQTS-type electrophysiological alterations of the cardiac sodium channel. | Wang Q | Journal of medical genetics | 2004 | PMID: 15121794 |
Nucleotide changes in the translated region of SCN5A from Japanese patients with Brugada syndrome and control subjects. | Takahata T | Life sciences | 2003 | PMID: 12639704 |
Genetic and biophysical basis of sudden unexplained nocturnal death syndrome (SUNDS), a disease allelic to Brugada syndrome. | Vatta M | Human molecular genetics | 2002 | PMID: 11823453 |
Genomic organization of the human SCN5A gene encoding the cardiac sodium channel. | Wang Q | Genomics | 1996 | PMID: 8661019 |
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Text-mined citations for rs41261344 ...
HelpRecord last updated Oct 13, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.