ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.677C>T (p.Ala226Val)
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.
Uncertain significance(6); Benign(1); Likely benign(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000335.5(SCN5A):c.677C>T (p.Ala226Val)
Variation ID: 68034 Accession: VCV000068034.25
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 38613769 (GRCh38) [ NCBI UCSC ] 3: 38655260 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jun 9, 2014 Feb 28, 2024 Jan 2, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000335.5:c.677C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000326.2:p.Ala226Val missense NM_001099404.2:c.703+206C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001099405.2:c.703+206C>T intron variant NM_001160160.2:c.703+206C>T intron variant NM_001160161.2:c.703+206C>T intron variant NM_001354701.2:c.703+206C>T intron variant NM_198056.3:c.677C>T NP_932173.1:p.Ala226Val missense NC_000003.12:g.38613769G>A NC_000003.11:g.38655260G>A NG_008934.1:g.40904C>T LRG_289:g.40904C>T LRG_289t1:c.677C>T LRG_289p1:p.Ala226Val Q14524:p.Ala226Val - Protein change
- A226V
- Other names
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- Canonical SPDI
- NC_000003.12:38613768: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) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00009
Exome Aggregation Consortium (ExAC) 0.00013
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
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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 |
3724 | 4156 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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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not provided (1) |
criteria provided, single submitter
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- | RCV000058837.18 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 16, 2016 | RCV000454727.13 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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May 28, 2019 | RCV000987236.19 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 28, 2017 | RCV001144461.13 | |
Benign (1) |
criteria provided, single submitter
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Apr 28, 2017 | RCV001144462.13 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 28, 2017 | RCV001144463.13 | |
Likely benign (1) |
criteria provided, single submitter
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Apr 28, 2017 | RCV001146371.13 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 28, 2017 | RCV001146370.13 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jan 2, 2024 | RCV001705715.12 | |
Likely benign (1) |
criteria provided, single submitter
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Nov 18, 2018 | RCV001842408.10 |
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
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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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Uncertain significance
(Dec 16, 2016)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000540294.1
First in ClinVar: Apr 09, 2017 Last updated: Apr 09, 2017 |
Comment:
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or … (more)
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported in an individual with Brugada syndrome who was compound het for this and an Arg1629X variant in SCN5A. Electrophysiological experiments showed that the variant had little effect on current density alone (Tan 2015). It was identified in 3 additional patients with Brugada syndrome. This variant is present in ClinVar with no classification. It has a Max MAF of 0.18% in ExAC (9 alleles) and 0.13% in gnomAD (25 alleles). This variant is predicted to be pathogenic by prediction tools. (less)
Method: Genome/Exome Filtration
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Uncertain significance
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Brugada syndrome 1
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001136486.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Likely benign
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Brugada syndrome 1
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001305061.1
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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Uncertain significance
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Sick sinus syndrome 1
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001305060.1
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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Benign
(Apr 28, 2017)
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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
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Illumina Laboratory Services, Illumina
Accession: SCV001305062.1
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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. (less)
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Uncertain significance
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Progressive familial heart block, type 1A
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001305063.1
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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Ventricular fibrillation, paroxysmal familial, type 1
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001307113.1
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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Likely benign
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Dilated cardiomyopathy 1E
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001307114.1
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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Likely benign
(Nov 18, 2018)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmia
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV001345532.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
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Likely benign
(Jan 02, 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: SCV000637202.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
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Uncertain significance
(Jul 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001820962.3
First in ClinVar: Sep 26, 2021 Last updated: Mar 04, 2023 |
Comment:
Published in vitro functional studies suggest a damaging effect (Tan et al., 2015; Ma et al., 2018); nevertheless, it is unclear how these studies may … (more)
Published in vitro functional studies suggest a damaging effect (Tan et al., 2015; Ma et al., 2018); nevertheless, it is unclear how these studies may translate to a pathogenic role in vivo; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20129283, 34649698, 24136861, 28779003, 14967853, 29728395, 30662450, 33195263, 30050137, 33071830, 25829473, 11901046) (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: SCV000090357.3
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:11901046;PMID:20129283). 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:11901046;PMID:20129283). 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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Likely pathogenic
(Mar 30, 2019)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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Brugada syndrome 1
Affected status: yes
Allele origin:
germline
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Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV001433335.1
First in ClinVar: Sep 24, 2020 Last updated: Sep 24, 2020 |
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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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A Brugada syndrome proband with compound heterozygote SCN5A mutations identified from a Chinese family in Singapore. | Tan BY | Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology | 2016 | PMID: 25829473 |
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 |
Natural history of Brugada syndrome: insights for risk stratification and management. | Priori SG | Circulation | 2002 | PMID: 11901046 |
Text-mined citations for rs199473561 ...
HelpRecord last updated Apr 20, 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.