ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.2204C>T (p.Ala735Val)
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.2204C>T (p.Ala735Val)
Variation ID: 9391 Accession: VCV000009391.6
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 38597787 (GRCh38) [ NCBI UCSC ] 3: 38639278 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jun 9, 2014 Sep 8, 2024 Jul 12, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000335.5:c.2204C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000326.2:p.Ala735Val missense NM_001099404.2:c.2204C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001092874.1:p.Ala735Val missense NM_001099405.2:c.2204C>T NP_001092875.1:p.Ala735Val missense NM_001160160.2:c.2204C>T NP_001153632.1:p.Ala735Val missense NM_001160161.2:c.2204C>T NP_001153633.1:p.Ala735Val missense NM_001354701.2:c.2204C>T NP_001341630.1:p.Ala735Val missense NM_198056.3:c.2204C>T NP_932173.1:p.Ala735Val missense NC_000003.12:g.38597787G>A NC_000003.11:g.38639278G>A NG_008934.1:g.56886C>T LRG_289:g.56886C>T LRG_289t1:c.2204C>T LRG_289p1:p.Ala735Val Q14524:p.Ala735Val - Protein change
- A735V
- Other names
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- Canonical SPDI
- NC_000003.12:38597786:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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SCN5A | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3779 | 4219 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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Likely pathogenic (2) |
criteria provided, single submitter
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- | RCV000009989.5 | |
not provided (1) |
criteria provided, single submitter
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- | RCV000058488.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jul 12, 2023 | RCV003591627.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 24, 2023 | RCV003654175.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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May 31, 2023 | RCV003996084.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Jul 12, 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: SCV004361693.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces alanine with valine at codon 735 of the SCN5A protein. This variant is found within a highly conserved region of the … (more)
This missense variant replaces alanine with valine at codon 735 of the SCN5A protein. This variant is found within a highly conserved region of the transmembrane domain DII. Rare nontruncating variants in this region (a.a. 718 - 9386) have been shown to be significantly overrepresented in individuals with Brugada syndrome (PMID: 32893267). Functional studies have shown that the variant affects sodium channel function (PMID: 11823453, 31371804). This variant has been reported in at least 7 unrelated individuals affected with Brugada syndrome (PMID: 17697823, 26921764, 28341781, 28491738, 29325976, 32893267, ClinVar SCV000545017.3), in an individual affected with cardiac sinus node dysfunction (PMID: 22795782), and in a few individuals suspected of having Brugada syndrome (PMID: 20129283). This variant has also been observed to segregate with abnormal ECG findings in three individuals from a family affected with sudden unexplained nocturnal death syndrome, a disease allelic to Brugada syndrome (PMID: 11823453). This variant has been identified in 1/249112 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
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Pathogenic
(Apr 24, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000545017.4
First in ClinVar: Jun 09, 2014 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SCN5A function (PMID: 11823453, 25348405, 26283144). … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SCN5A function (PMID: 11823453, 25348405, 26283144). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 9391). This missense change has been observed in individuals with sudden unexplained nocturnal death syndrome and Brugada syndrome (PMID: 11823453, 17697823, 20129283, 30193851). This variant is present in population databases (rs137854611, gnomAD 0.006%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 735 of the SCN5A protein (p.Ala735Val). (less)
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Likely Pathogenic
(May 31, 2023)
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criteria provided, single submitter
Method: clinical testing
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Congenital long QT syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004827566.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
The c.2204C>T (p.Ala735Val) variant in the SCN5A gene is located on the exon 14 and is predicted to replace alanine with valine at codon 735 … (more)
The c.2204C>T (p.Ala735Val) variant in the SCN5A gene is located on the exon 14 and is predicted to replace alanine with valine at codon 735 (p.Ala735Val). The variant has been reported in multiple individuals with Brugada syndrome, in one individual with cardiac sinus node dysfunction and in one individual with dilated cardiomyopathy/other cardiac disease (PMID: 11823453, 17697823, 20129283, 22795782, 36129056, 28491738). The variant has been reported to segregate with Brugada syndrome in one family (PMID: 11823453). Electrophysiological experiments of this variant reported the negative functional impact (PMID: 11823453, 26283144). The variant is reported in ClinVar (ID: 9391). This variant is rare in the general population according to gnomAD (1/249112). Computational prediction algorithms suggest a deleterious impact for this variant (REVEL score 0.943). Therefore, the c.2204C>T (p.Ala735Val) variant of SCN5A has been classified as likely pathogenic. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Brugada syndrome 1
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
paternal
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Institute for Human Genetics and Genomic Medicine, Uniklinik RWTH Aachen
Accession: SCV005201047.1
First in ClinVar: Sep 08, 2024 Last updated: Sep 08, 2024 |
Comment:
The variant is present in the general population with a frequency of 0,000123%. Bioinformatic prediticon anticipate a deleterious effect, and it has been reported in … (more)
The variant is present in the general population with a frequency of 0,000123%. Bioinformatic prediticon anticipate a deleterious effect, and it has been reported in patients with Brugada-syndrome before. (less)
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Pathogenic
(Feb 01, 2002)
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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
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OMIM
Accession: SCV000030210.3
First in ClinVar: Apr 04, 2013 Last updated: Nov 18, 2016 |
Comment on evidence:
In a family with SUNDS, a disorder identical to Brugada syndrome (BRGDA1; 601144), that exhibited autosomal dominant inheritance, Vatta et al. (2002) identified among affected … (more)
In a family with SUNDS, a disorder identical to Brugada syndrome (BRGDA1; 601144), that exhibited autosomal dominant inheritance, Vatta et al. (2002) identified among affected members a 2204C-T transition, which is predicted to result in an ala735-to-val (A735V) substitution. The mutation lies in the first transmembrane segment of domain II, (DIIS1), close to the first extracellular loop between DIIS1 and DIIS2. In transfected Xenopus oocytes, the A735V mutant expressed currents with steady-state activation voltage shifted to more positive potentials and exhibited reduced sodium channel current at the end of phase I of the action potential. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Brugada syndrome
Affected status: unknown
Allele origin:
germline
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Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust
Accession: SCV000090008.3
First in ClinVar: Oct 22, 2013 Last updated: Jun 09, 2014 |
Comment:
This variant has been reported as associated with Brugada syndrome in the following publications (PMID:11823453;PMID:20129283;PMID:22795782). This is a literature report, and does not necessarily reflect … (more)
This variant has been reported as associated with Brugada syndrome in the following publications (PMID:11823453;PMID:20129283;PMID:22795782). 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 |
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Determining the Likelihood of Disease Pathogenicity Among Incidentally Identified Genetic Variants in Rare Dilated Cardiomyopathy-Associated Genes. | Yang Q | Journal of the American Heart Association | 2022 | PMID: 36129056 |
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 |
Comparing human iPSC-cardiomyocytes versus HEK293T cells unveils disease-causing effects of Brugada mutation A735V of Na(V)1.5 sodium channels. | de la Roche J | Scientific reports | 2019 | PMID: 31371804 |
Clinical presentation and follow-up of women affected by Brugada syndrome. | Berthome P | Heart rhythm | 2019 | PMID: 30193851 |
Profile of patients with Brugada syndrome presenting with their first documented arrhythmic event: Data from the Survey on Arrhythmic Events in BRUgada Syndrome (SABRUS). | Milman A | Heart rhythm | 2018 | PMID: 29325976 |
Genotype-Phenotype Correlation of SCN5A Mutation for the Clinical and Electrocardiographic Characteristics of Probands With Brugada Syndrome: A Japanese Multicenter Registry. | Yamagata K | Circulation | 2017 | PMID: 28341781 |
IRX3 variant as a modifier of Brugada syndrome with frequent ventricular fibrillation. | Kimura Y | HeartRhythm case reports | 2016 | PMID: 28491738 |
Impact of clinical and genetic findings on the management of young patients with Brugada syndrome. | Andorin A | Heart rhythm | 2016 | PMID: 26921764 |
Direct Measurement of Cardiac Na+ Channel Conformations Reveals Molecular Pathologies of Inherited Mutations. | Varga Z | Circulation. Arrhythmia and electrophysiology | 2015 | PMID: 26283144 |
UniProt: a hub for protein information. | UniProt Consortium | Nucleic acids research | 2015 | PMID: 25348405 |
[Cardiac sinus node dysfunction due to a new mutation of the SCN5A gene]. | Selly JB | Archives de pediatrie : organe officiel de la Societe francaise de pediatrie | 2012 | PMID: 22795782 |
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 |
Comparison of long-term follow-up of electrocardiographic features in Brugada syndrome between the SCN5A-positive probands and the SCN5A-negative probands. | Yokokawa M | The American journal of cardiology | 2007 | PMID: 17697823 |
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 |
[Breech delivery in the Sibenik Maternity Hospital (author's transl)]. | Merlak I | Lijecnicki vjesnik | 1979 | PMID: 545017 |
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Text-mined citations for rs137854611 ...
HelpRecord last updated Sep 29, 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.