The SCN5A c.3784G>A (p.Gly1262Ser) missense variant has been reported in two studies in which it is found in a total of seven individuals in a heterozygous state, including in one proband with Brugada syndrome, the proband's affected brother and as yet two unaffected children, in one additional unrelated individual with Brugada syndrome, in one individual diagnosed with dilated cardiomyopathy, and in one individual diagnosed with hypertrophic cardiomyopathy (Shin et al. 2004; Priganc et al. 2016). The p.Gly1262Ser variant was absent from 352 control chromosomes, but is reported at a frequency of 0.00013 in the South Asian population of the Genome Aggregation Database. Based on the evidence, the p.Gly1262Ser variant is classified as a variant of uncertain significance but suspicious for pathogenicity for SCN5A-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.3781G>A (p.Gly1261Ser)
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.
(13)
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.
Conflicting classifications of pathogenicity
Likely pathogenic(1); Uncertain significance(10)
Likely pathogenic(1); Uncertain significance(10)
13
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000335.5(SCN5A):c.3781G>A (p.Gly1261Ser)
Variation ID: 9399 Accession: VCV000009399.13
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3p22.2 3: 38566465 (GRCh38) [ NCBI UCSC ] 3: 38607956 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jun 9, 2014 May 1, 2024 Jul 28, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000335.5:c.3781G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000326.2:p.Gly1261Ser missense NM_001099404.2:c.3784G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001092874.1:p.Gly1262Ser missense NM_001099405.2:c.3784G>A NP_001092875.1:p.Gly1262Ser missense NM_001160160.2:c.3781G>A NP_001153632.1:p.Gly1261Ser missense NM_001160161.2:c.3622G>A NP_001153633.1:p.Gly1208Ser missense NM_001354701.2:c.3781G>A NP_001341630.1:p.Gly1261Ser missense NM_198056.3:c.3784G>A NP_932173.1:p.Gly1262Ser missense NC_000003.12:g.38566465C>T NC_000003.11:g.38607956C>T NG_008934.1:g.88208G>A LRG_289:g.88208G>A LRG_289t1:c.3784G>A LRG_289p1:p.Gly1262Ser LRG_289t2:c.3781G>A LRG_289p2:p.Gly1261Ser - Protein change
- G1262S, G1261S, G1208S
- Other names
- -
- Canonical SPDI
- NC_000003.12:38566464:C:T
-
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) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00003
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 |
3773 | 4212 | |
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. |
|---|---|---|---|---|
| Likely pathogenic (2) |
criteria provided, single submitter
|
Feb 21, 2020 | RCV000010001.7 | |
| not provided (1) |
criteria provided, single submitter
|
- | RCV000058602.6 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Nov 21, 2018 | RCV000755698.7 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Jul 28, 2023 | RCV001753410.5 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Apr 7, 2022 | RCV004018613.1 | |
|
SCN5A-related disorder
|
Uncertain significance (1) |
criteria provided, single submitter
|
Apr 28, 2017 | RCV004528100.1 |
| Uncertain significance (1) |
criteria provided, single submitter
|
Apr 28, 2017 | RCV001146725.5 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Apr 28, 2017 | RCV001146726.5 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Apr 28, 2017 | RCV001146727.5 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
May 4, 2023 | RCV003996086.2 |
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
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
(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: SCV000883130.1
First in ClinVar: Feb 18, 2019 Last updated: Feb 18, 2019 |
|
|
|
Uncertain significance
(Apr 28, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
SCN5A-Related Disorders
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000916019.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The SCN5A c.3784G>A (p.Gly1262Ser) missense variant has been reported in two studies in which it is found in a total of seven individuals in a … (more)
The SCN5A c.3784G>A (p.Gly1262Ser) missense variant has been reported in two studies in which it is found in a total of seven individuals in a heterozygous state, including in one proband with Brugada syndrome, the proband's affected brother and as yet two unaffected children, in one additional unrelated individual with Brugada syndrome, in one individual diagnosed with dilated cardiomyopathy, and in one individual diagnosed with hypertrophic cardiomyopathy (Shin et al. 2004; Priganc et al. 2016). The p.Gly1262Ser variant was absent from 352 control chromosomes, but is reported at a frequency of 0.00013 in the South Asian population of the Genome Aggregation Database. Based on the evidence, the p.Gly1262Ser variant is classified as a variant of uncertain significance but suspicious for pathogenicity for SCN5A-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
|
|
|
Uncertain significance
(Apr 28, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Progressive familial heart block, type 1A
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001307479.1
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)
|
|
|
Uncertain significance
(Apr 28, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Ventricular fibrillation, paroxysmal familial, type 1
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001307480.1
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)
|
|
|
Uncertain significance
(Apr 28, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Sick sinus syndrome 1
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001307482.1
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)
|
|
|
Uncertain significance
(Apr 28, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Long QT syndrome 3
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001307481.1
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)
|
|
|
Likely pathogenic
(Feb 21, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Brugada syndrome 1
Affected status: yes
Allele origin:
unknown
|
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues
Accession: SCV001422293.1
First in ClinVar: Jul 16, 2020 Last updated: Jul 16, 2020 |
|
|
|
Uncertain significance
(Nov 27, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001985375.2
First in ClinVar: Nov 06, 2021 Last updated: Mar 04, 2023 |
Comment:
Reported in individuals with DCM and HCM (Priganc et al., 2016), an individual referred for Brugada syndrome testing (Kapplinger et al., 2010), and a child … (more)
Reported in individuals with DCM and HCM (Priganc et al., 2016), an individual referred for Brugada syndrome testing (Kapplinger et al., 2010), and a child with noncompaction cardiomyopathy (van Waning et al., 2018); Reported in ClinVar as a variant of uncertain significance by other clinical laboratories (ClinVar Variant ID#9399; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32048431, 31677787, 24903439, 19336922, 22581653, 18436145, 19027780, 15338453, 27554632, 29447731, 30662450, 20129283, 24136861, 31019283, 30193851, 31737537, 32533946, 33131149) (less)
|
|
|
Uncertain significance
(Jul 28, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000825694.3
First in ClinVar: Oct 10, 2018 Last updated: Feb 28, 2024 |
Comment:
Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 32533946) indicates that this missense variant is expected to disrupt SCN5A … (more)
Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 32533946) indicates that this missense variant is expected to disrupt SCN5A function. Experimental studies have shown that this missense change affects SCN5A function (PMID: 32533946). 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. This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1262 of the SCN5A protein (p.Gly1262Ser). This variant is present in population databases (rs137854616, gnomAD 0.01%). This missense change has been observed in individual(s) with Brugada syndrome and/or dilated cardiomyopathy or hypertrophic cardiomyopathy and Brugada syndrome (PMID: 15338453, 20129283, 27554632, 30193851). ClinVar contains an entry for this variant (Variation ID: 9399). (less)
|
|
|
Uncertain Significance
(May 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiac arrhythmia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004831376.1
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)
|
Comment:
This missense variant replaces glycine with serine at codon 1262 of the SCN5A protein. This variant is also known as c.3781G>A (p.Gly1261Ser) based on a … (more)
This missense variant replaces glycine with serine at codon 1262 of the SCN5A protein. This variant is also known as c.3781G>A (p.Gly1261Ser) based on a different transcript NM_000335.5. 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 three individuals affected with Brugada syndrome including two who were from the same family (PMID: 15338453, 20129283), two individuals affected with dilated cardiomyopathy and one individual with hypertrophic cardiomyopathy (PMID: 27554632), and in another individual affected with noncompaction cardiomyopathy and atrial fibrillation (Van Waning 2020, dissertation, Erasmus University Rotterdam). This variant has been identified in 8/282850 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)
Number of individuals with the variant: 2
|
|
|
Uncertain significance
(Apr 07, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV004943834.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
The c.3784G>A (p.G1262S) alteration is located in exon 21 (coding exon 20) of the SCN5A gene. This alteration results from a G to A substitution … (more)
The c.3784G>A (p.G1262S) alteration is located in exon 21 (coding exon 20) of the SCN5A gene. This alteration results from a G to A substitution at nucleotide position 3784, causing the glycine (G) at amino acid position 1262 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
|
|
|
Pathogenic
(Jan 01, 2004)
|
no assertion criteria provided
Method: literature only
|
BRUGADA SYNDROME 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000030222.2
First in ClinVar: Apr 04, 2013 Last updated: Nov 14, 2016 |
Comment on evidence:
Shin et al. (2004) studied a family with 9 members as well as 12 unrelated sporadic cases, all Koreans, diagnosed with Brugada syndrome (BRGDA1; 601144). … (more)
Shin et al. (2004) studied a family with 9 members as well as 12 unrelated sporadic cases, all Koreans, diagnosed with Brugada syndrome (BRGDA1; 601144). They identified a novel missense mutation associated with Brugada syndrome in the family: a single-nucleotide substitution of G to A at nucleotide position 3934 in exon 21 of the SCN5A gene that changed glycine-1262 to serine (G1262S) in segment 2 of domain III of the SCN5A protein. Four individuals in the family carried the identical mutation, but none of the 12 sporadic patients did. The mutation was not found in 150 unrelated normal individuals. (less)
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Brugada syndrome
Affected status: unknown
Allele origin:
germline
|
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust
Accession: SCV000090122.3
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:15338453;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:15338453;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)
|
|
| click to load more click to collapse | |||||
Comment:
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, 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.
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, 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.
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, 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.
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, 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.
Comment:
Reported in individuals with DCM and HCM (Priganc et al., 2016), an individual referred for Brugada syndrome testing (Kapplinger et al., 2010), and a child with noncompaction cardiomyopathy (van Waning et al., 2018); Reported in ClinVar as a variant of uncertain significance by other clinical laboratories (ClinVar Variant ID#9399; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32048431, 31677787, 24903439, 19336922, 22581653, 18436145, 19027780, 15338453, 27554632, 29447731, 30662450, 20129283, 24136861, 31019283, 30193851, 31737537, 32533946, 33131149)
Comment:
Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 32533946) indicates that this missense variant is expected to disrupt SCN5A function. Experimental studies have shown that this missense change affects SCN5A function (PMID: 32533946). 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. This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1262 of the SCN5A protein (p.Gly1262Ser). This variant is present in population databases (rs137854616, gnomAD 0.01%). This missense change has been observed in individual(s) with Brugada syndrome and/or dilated cardiomyopathy or hypertrophic cardiomyopathy and Brugada syndrome (PMID: 15338453, 20129283, 27554632, 30193851). ClinVar contains an entry for this variant (Variation ID: 9399).
Comment:
This missense variant replaces glycine with serine at codon 1262 of the SCN5A protein. This variant is also known as c.3781G>A (p.Gly1261Ser) based on a different transcript NM_000335.5. 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 three individuals affected with Brugada syndrome including two who were from the same family (PMID: 15338453, 20129283), two individuals affected with dilated cardiomyopathy and one individual with hypertrophic cardiomyopathy (PMID: 27554632), and in another individual affected with noncompaction cardiomyopathy and atrial fibrillation (Van Waning 2020, dissertation, Erasmus University Rotterdam). This variant has been identified in 8/282850 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 c.3784G>A (p.G1262S) alteration is located in exon 21 (coding exon 20) of the SCN5A gene. This alteration results from a G to A substitution at nucleotide position 3784, causing the glycine (G) at amino acid position 1262 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Comment:
This variant has been reported as associated with Brugada syndrome in the following publications (PMID:15338453;PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
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:
The SCN5A c.3784G>A (p.Gly1262Ser) missense variant has been reported in two studies in which it is found in a total of seven individuals in a heterozygous state, including in one proband with Brugada syndrome, the proband's affected brother and as yet two unaffected children, in one additional unrelated individual with Brugada syndrome, in one individual diagnosed with dilated cardiomyopathy, and in one individual diagnosed with hypertrophic cardiomyopathy (Shin et al. 2004; Priganc et al. 2016). The p.Gly1262Ser variant was absent from 352 control chromosomes, but is reported at a frequency of 0.00013 in the South Asian population of the Genome Aggregation Database. Based on the evidence, the p.Gly1262Ser variant is classified as a variant of uncertain significance but suspicious for pathogenicity for SCN5A-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
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, 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.
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, 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.
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, 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.
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, 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.
Comment:
Reported in individuals with DCM and HCM (Priganc et al., 2016), an individual referred for Brugada syndrome testing (Kapplinger et al., 2010), and a child with noncompaction cardiomyopathy (van Waning et al., 2018); Reported in ClinVar as a variant of uncertain significance by other clinical laboratories (ClinVar Variant ID#9399; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32048431, 31677787, 24903439, 19336922, 22581653, 18436145, 19027780, 15338453, 27554632, 29447731, 30662450, 20129283, 24136861, 31019283, 30193851, 31737537, 32533946, 33131149)
Comment:
Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 32533946) indicates that this missense variant is expected to disrupt SCN5A function. Experimental studies have shown that this missense change affects SCN5A function (PMID: 32533946). 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. This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1262 of the SCN5A protein (p.Gly1262Ser). This variant is present in population databases (rs137854616, gnomAD 0.01%). This missense change has been observed in individual(s) with Brugada syndrome and/or dilated cardiomyopathy or hypertrophic cardiomyopathy and Brugada syndrome (PMID: 15338453, 20129283, 27554632, 30193851). ClinVar contains an entry for this variant (Variation ID: 9399).
Comment:
This missense variant replaces glycine with serine at codon 1262 of the SCN5A protein. This variant is also known as c.3781G>A (p.Gly1261Ser) based on a different transcript NM_000335.5. 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 three individuals affected with Brugada syndrome including two who were from the same family (PMID: 15338453, 20129283), two individuals affected with dilated cardiomyopathy and one individual with hypertrophic cardiomyopathy (PMID: 27554632), and in another individual affected with noncompaction cardiomyopathy and atrial fibrillation (Van Waning 2020, dissertation, Erasmus University Rotterdam). This variant has been identified in 8/282850 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 c.3784G>A (p.G1262S) alteration is located in exon 21 (coding exon 20) of the SCN5A gene. This alteration results from a G to A substitution at nucleotide position 3784, causing the glycine (G) at amino acid position 1262 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Comment:
This variant has been reported as associated with Brugada syndrome in the following publications (PMID:15338453;PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| High-Throughput Reclassification of SCN5A Variants. | Glazer AM | American journal of human genetics | 2020 | PMID: 32533946 |
| Clinical presentation and follow-up of women affected by Brugada syndrome. | Berthome P | Heart rhythm | 2019 | PMID: 30193851 |
| Analysis of SCN5A Gene Variants in East Slovak Patients with Cardiomyopathy. | Priganc M | Journal of clinical laboratory analysis | 2017 | PMID: 27554632 |
| 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 analysis of the cardiac sodium channel gene SCN5A in Koreans with Brugada syndrome. | Shin DJ | Journal of human genetics | 2004 | PMID: 15338453 |
Text-mined citations for rs137854616 ...
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 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.