This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1357 of the SCN5A protein (p.Ala1357Val). This variant is present in population databases (rs370588133, gnomAD 0.03%). This missense change has been observed in individual(s) with SCN5A-related conditions (PMID: 23631430, 30193851). ClinVar contains an entry for this variant (Variation ID: 201505). 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 disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.4067C>T (p.Ala1356Val)
Germline
Classification
Help
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.
(7)
Help
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
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000335.5(SCN5A):c.4067C>T (p.Ala1356Val)
Variation ID: 201505 Accession: VCV000201505.39
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 38560322 (GRCh38) [ NCBI UCSC ] 3: 38601813 (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 Jul 5, 2015 Oct 20, 2024 Nov 1, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000335.5:c.4067C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000326.2:p.Ala1356Val missense NM_001099404.2:c.4070C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001092874.1:p.Ala1357Val missense NM_001099405.2:c.4070C>T NP_001092875.1:p.Ala1357Val missense NM_001160160.2:c.4067C>T NP_001153632.1:p.Ala1356Val missense NM_001160161.2:c.3908C>T NP_001153633.1:p.Ala1303Val missense NM_001354701.2:c.4067C>T NP_001341630.1:p.Ala1356Val missense NM_198056.3:c.4070C>T NP_932173.1:p.Ala1357Val missense NC_000003.12:g.38560322G>A NC_000003.11:g.38601813G>A NG_008934.1:g.94351C>T LRG_289:g.94351C>T LRG_289t1:c.4070C>T LRG_289p1:p.Ala1357Val - Protein change
- A1356V, A1357V, A1303V
- Other names
-
p.A1357V:GCG>GTG
- Canonical SPDI
- NC_000003.12:38560321:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00006
The Genome Aggregation Database (gnomAD) 0.00007
Exome Aggregation Consortium (ExAC) 0.00008
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00008
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| SCN5A | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3783 | 4225 | |
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. |
|---|---|---|---|---|
| Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Nov 1, 2023 | RCV000183061.32 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Aug 26, 2022 | RCV000617866.11 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
May 28, 2019 | RCV000987203.9 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Jan 27, 2023 | RCV001842920.11 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
May 17, 2022 | RCV003150057.9 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Brugada syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001136452.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
|
|
Uncertain significance
(Nov 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000545037.7
First in ClinVar: Apr 17, 2017 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1357 of the SCN5A protein (p.Ala1357Val). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1357 of the SCN5A protein (p.Ala1357Val). This variant is present in population databases (rs370588133, gnomAD 0.03%). This missense change has been observed in individual(s) with SCN5A-related conditions (PMID: 23631430, 30193851). ClinVar contains an entry for this variant (Variation ID: 201505). 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 disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
|
|
Uncertain significance
(Jan 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiac arrhythmia
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV001343058.2
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces alanine with valine at codon 1357 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces alanine with valine at codon 1357 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a few individuals affected with Brugada syndrome (PMID: 30193851, 32893267), in an individual affected with catecholaminergic polymorphic ventricular tachycardia (PMID: 35663620), and in an individual suspected of having long QT syndrome testing (PMID: 23631430). This variant has also been identified in 19/282878 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
|
|
|
Uncertain significance
(Aug 26, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000736313.5
First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024 |
Comment:
The p.A1357V variant (also known as c.4070C>T), located in coding exon 22 of the SCN5A gene, results from a C to T substitution at nucleotide … (more)
The p.A1357V variant (also known as c.4070C>T), located in coding exon 22 of the SCN5A gene, results from a C to T substitution at nucleotide position 4070. The alanine at codon 1357 is replaced by valine, an amino acid with similar properties, and is located in the DIII/S5 region of the protein. This alteration was reported in an individual with suspected diagnosis of long QT syndrome; however, clinical details were limited (Lieve KV et al. Genet Test Mol Biomarkers. 2013;17:553-61). This alteration has also been seen in an exome cohort and in one ostensibly healthy individual (Kapplinger JD et al. Circ Cardiovasc Genet, 2015 Aug;8:582-95; Maxwell KN et al. Am. J. Hum. Genet., 2016 May;98:801-817). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
|
|
|
Uncertain significance
(Sep 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001962481.20
First in ClinVar: Oct 08, 2021 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
|
|
Uncertain significance
(May 17, 2022)
|
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: SCV003838218.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
|
|
|
Likely pathogenic
(May 05, 2014)
|
Flagged submission
flagged submission
Method: clinical testing
Reason: Older claim that does not account for recent evidence
Source: ClinGen
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000235470.8
First in ClinVar: Jul 05, 2015 Last updated: Jul 05, 2015 |
Comment:
The A1357V variant that is likely pathogenic in the SCN5A gene has been reported previously in one patient with LQTS, and was not reported in … (more)
The A1357V variant that is likely pathogenic in the SCN5A gene has been reported previously in one patient with LQTS, and was not reported in at least 600 control alleles (Lieve K et al., 2013). The A1357V variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. This substitution occurs at a position that is conserved across species. Furthermore, missense mutations in nearby residues (M1351R, V1353M G1358W, K1359N) have been reported in association with Brugada, supporting the functional importance of this region of the protein. Nevertheless, the A1357V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded.The variant is found in CARDIOMYOPATHY panel(s). (less)
|
|
| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Comment:
Comment:
This missense variant replaces alanine with valine at codon 1357 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a few individuals affected with Brugada syndrome (PMID: 30193851, 32893267), in an individual affected with catecholaminergic polymorphic ventricular tachycardia (PMID: 35663620), and in an individual suspected of having long QT syndrome testing (PMID: 23631430). This variant has also been identified in 19/282878 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
The p.A1357V variant (also known as c.4070C>T), located in coding exon 22 of the SCN5A gene, results from a C to T substitution at nucleotide position 4070. The alanine at codon 1357 is replaced by valine, an amino acid with similar properties, and is located in the DIII/S5 region of the protein. This alteration was reported in an individual with suspected diagnosis of long QT syndrome; however, clinical details were limited (Lieve KV et al. Genet Test Mol Biomarkers. 2013;17:553-61). This alteration has also been seen in an exome cohort and in one ostensibly healthy individual (Kapplinger JD et al. Circ Cardiovasc Genet, 2015 Aug;8:582-95; Maxwell KN et al. Am. J. Hum. Genet., 2016 May;98:801-817). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
The A1357V variant that is likely pathogenic in the SCN5A gene has been reported previously in one patient with LQTS, and was not reported in at least 600 control alleles (Lieve K et al., 2013). The A1357V variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. This substitution occurs at a position that is conserved across species. Furthermore, missense mutations in nearby residues (M1351R, V1353M G1358W, K1359N) have been reported in association with Brugada, supporting the functional importance of this region of the protein. Nevertheless, the A1357V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded.The variant is found in CARDIOMYOPATHY panel(s).
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. |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1357 of the SCN5A protein (p.Ala1357Val). This variant is present in population databases (rs370588133, gnomAD 0.03%). This missense change has been observed in individual(s) with SCN5A-related conditions (PMID: 23631430, 30193851). ClinVar contains an entry for this variant (Variation ID: 201505). 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 disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
This missense variant replaces alanine with valine at codon 1357 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a few individuals affected with Brugada syndrome (PMID: 30193851, 32893267), in an individual affected with catecholaminergic polymorphic ventricular tachycardia (PMID: 35663620), and in an individual suspected of having long QT syndrome testing (PMID: 23631430). This variant has also been identified in 19/282878 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
The p.A1357V variant (also known as c.4070C>T), located in coding exon 22 of the SCN5A gene, results from a C to T substitution at nucleotide position 4070. The alanine at codon 1357 is replaced by valine, an amino acid with similar properties, and is located in the DIII/S5 region of the protein. This alteration was reported in an individual with suspected diagnosis of long QT syndrome; however, clinical details were limited (Lieve KV et al. Genet Test Mol Biomarkers. 2013;17:553-61). This alteration has also been seen in an exome cohort and in one ostensibly healthy individual (Kapplinger JD et al. Circ Cardiovasc Genet, 2015 Aug;8:582-95; Maxwell KN et al. Am. J. Hum. Genet., 2016 May;98:801-817). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
The A1357V variant that is likely pathogenic in the SCN5A gene has been reported previously in one patient with LQTS, and was not reported in at least 600 control alleles (Lieve K et al., 2013). The A1357V variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. This substitution occurs at a position that is conserved across species. Furthermore, missense mutations in nearby residues (M1351R, V1353M G1358W, K1359N) have been reported in association with Brugada, supporting the functional importance of this region of the protein. Nevertheless, the A1357V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded.The variant is found in CARDIOMYOPATHY panel(s).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Deadly emotional argument: Sudden cardiac death in catecholaminergic polymorphic ventricular tachycardia (CPVT). | Violano M | International journal of cardiology. Heart & vasculature | 2022 | PMID: 35663620 |
| 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 |
| Diagnostic power and clinical impact of exome sequencing in a cohort of 500 patients with rare diseases. | Quaio CRDC | American journal of medical genetics. Part C, Seminars in medical genetics | 2020 | PMID: 33258288 |
| Clinical presentation and follow-up of women affected by Brugada syndrome. | Berthome P | Heart rhythm | 2019 | PMID: 30193851 |
| Distinguishing pathogenic mutations from background genetic noise in cardiology: The use of large genome databases for genetic interpretation. | Ghouse J | Clinical genetics | 2018 | PMID: 28589536 |
| 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 |
| Enhanced Classification of Brugada Syndrome-Associated and Long-QT Syndrome-Associated Genetic Variants in the SCN5A-Encoded Na(v)1.5 Cardiac Sodium Channel. | Kapplinger JD | Circulation. Cardiovascular genetics | 2015 | PMID: 25904541 |
| 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 |
| Results of genetic testing in 855 consecutive unrelated patients referred for long QT syndrome in a clinical laboratory. | Lieve KV | Genetic testing and molecular biomarkers | 2013 | PMID: 23631430 |
Text-mined citations for rs370588133 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 10, 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.