ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.5827C>T (p.Arg1943Ter)
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.
Likely pathogenic(4); Uncertain significance(5)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000335.5(SCN5A):c.5827C>T (p.Arg1943Ter)
Variation ID: 201596 Accession: VCV000201596.27
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3p22.2 3: 38550542 (GRCh38) [ NCBI UCSC ] 3: 38592033 (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 Dec 6, 2016 May 1, 2024 Jan 2, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000335.5:c.5827C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000326.2:p.Arg1943Ter nonsense NM_001099404.2:c.5830C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001092874.1:p.Arg1944Ter nonsense NM_001099405.2:c.5776C>T NP_001092875.1:p.Arg1926Ter nonsense NM_001160160.2:c.5731C>T NP_001153632.1:p.Arg1911Ter nonsense NM_001160161.2:c.5668C>T NP_001153633.1:p.Arg1890Ter nonsense NM_001354701.2:c.5773C>T NP_001341630.1:p.Arg1925Ter nonsense NM_198056.3:c.5830C>T NP_932173.1:p.Arg1944Ter nonsense NC_000003.12:g.38550542G>A NC_000003.11:g.38592033G>A NG_008934.1:g.104131C>T LRG_289:g.104131C>T LRG_289t1:c.5830C>T LRG_289p1:p.Arg1944Ter LRG_289t3:c.5830C>T LRG_289p3:p.Arg1944Ter - Protein change
- R1943*, R1944*, R1890*, R1911*, R1925*, R1926*
- Other names
- p.R1944*:CGA>TGA
- Canonical SPDI
- NC_000003.12:38550541: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 0.00001
The Genome Aggregation Database (gnomAD) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00009
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 |
3739 | 4175 |
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. |
---|---|---|---|---|
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
|
Jan 2, 2024 | RCV000183202.18 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
- | RCV000363289.15 | |
Likely pathogenic (2) |
criteria provided, single submitter
|
- | RCV000844965.10 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Jan 2, 2024 | RCV002354485.10 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Mar 22, 2023 | RCV001842941.11 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Oct 12, 2023 | RCV003398912.1 |
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. |
|
---|---|---|---|---|---|
Likely pathogenic
(Sep 17, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002502737.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
|
|
Uncertain significance
(Nov 15, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
unknown
|
Illumina Laboratory Services, Illumina
Accession: SCV003802865.1
First in ClinVar: Feb 18, 2023 Last updated: Feb 18, 2023 |
Comment:
The SCN5A c.5830C>T (p.Arg1944Ter) nonsense variant results in the substitution of arginine at amino acid position 1944 with a stop codon. This variant occurs in … (more)
The SCN5A c.5830C>T (p.Arg1944Ter) nonsense variant results in the substitution of arginine at amino acid position 1944 with a stop codon. This variant occurs in the last exon of the gene and may escape nonsense-mediated mRNA decay. This variant has been reported in a heterozygous state in at least three individuals in the literature, including a proband with Brugada syndrome (PMID: 33221895), and two female infants with sudden infant death syndrome, one of whom carried a second missense variant in SCN5A (PMID: 28370132; PMID: 29247119; PMID: 24631775). This variant is reported in the Genome Aggregation Database in four alleles at a frequency of 0.000262 in the Latino/Admixed American population (version 3.1.2). This frequency is high but may be consistent with reduced penetrance. Patch clamp studies in HEK293 cells overexpressing the Arg1944Ter mutant protein demonstrated no significant alteration in Na(v)1.5 channel kinetics compared to the wild type protein (PMID: 28370132). Based on the available evidence, the c.5830C>T (p.Arg1944Ter) variant is classified as a variant of uncertain significance for SCN5A-related disorders. (less)
|
|
Likely pathogenic
(Aug 08, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000235621.13
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
Identified in the literature in an infant with sudden unexplained (Wang et al., 2014) and in an individual with Brugada syndrome (Ciconte et al., 2021); … (more)
Identified in the literature in an infant with sudden unexplained (Wang et al., 2014) and in an individual with Brugada syndrome (Ciconte et al., 2021); however, both patients also harbored an additional variant in the SCN5A gene and no segregation data was reported; Identified by clinical exome sequencing in a patient with skeletal muscle involvement but no evidence of cardiac involvement in the literature (Monies et al., 2019); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 73 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29247119, 28316956, 28370132, 31698696, 33221895, 24631775, 31130284) (less)
|
|
Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
SCN5A-Related Disorders
Affected status: yes
Allele origin:
germline
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV004046047.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
This nonsense variant is found in the last exon of SCN5A and is predicted to cause loss of normal protein function by protein truncation with … (more)
This nonsense variant is found in the last exon of SCN5A and is predicted to cause loss of normal protein function by protein truncation with loss of the last 73 amino acids of the protein. Another nonsense variant located downstream of this variant has been reported in individuals with SCN5A-related disorders (PMID: 23538271, 28600387, 31447099, 27532257, 19862833). Loss of function variation in SCN5A is an established mechanism of disease (PMID: 14523039, 35305865, 20301690). This variant has been previously reported as a heterozygous change in individuals with cardiac arrhythmia and sudden unexplained death (PMID: 24631775, 28370132, 29247119). However, the individual with sudden unexplained death was reported to have an additional variant in the SCN5A gene and segregation data was not available (PMID: 24631775).The c.5830C>T (p.Arg1944Ter) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.001% (4/279424) and thus is presumed to be rare. Based on the available evidence, the c.5830C>T (p.Arg1944Ter) variant is classified as Likely Pathogenic. (less)
|
|
Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
SCN5A related disorder
Affected status: yes
Allele origin:
germline
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV004046137.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
This nonsense variant is found in the last exon of SCN5A and is predicted to cause loss of normal protein function by protein truncation with … (more)
This nonsense variant is found in the last exon of SCN5A and is predicted to cause loss of normal protein function by protein truncation with loss of the last 73 amino acids of the protein. This variant has been previously reported as a heterozygous change in patients with cardiac arrhythmia (PMID: 29247119) and sudden unexplained death (SUD) (PMID: 24631775). However, the patient with SUD harbored an additional variant in the SCN5A gene, and segregation data was not available (PMID: 24631775). One other nonsense variant located downstream of this variant has been reported as disease-causing in the literature (PMID: 23538271, 28600387, 31447099, 27532257, 19862833), and loss of function is a known mechanism of disease in the SCN5A gene. It is present in the heterozygous state in the gnomAD population database at a frequency of 0.001% (4/279424) and thus is presumed to be rare. Based on the available evidence, the c.5830C>T (p.Arg1944Ter) variant is classified as Likely Pathogenic. (less)
|
|
Uncertain significance
(Oct 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004122838.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
Variant summary: SCN5A c.5830C>T (p.Arg1944X), located within the last exon, results in a premature termination codon and is predicted to cause a truncation of the … (more)
Variant summary: SCN5A c.5830C>T (p.Arg1944X), located within the last exon, results in a premature termination codon and is predicted to cause a truncation of the encoded protein but is not expected to undergo nonsense mediated decay. The variant allele was found at a frequency of 1.2e-05 in 248022 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5830C>T has been reported in the literature in a case of sudden unexplained death in an infant (Wang_2017, Lin_2017), and in an individual with Brugada syndrome, who also harbored a second putatively pathogenic variant in SCN5A (Ciconte_2021). The variant has also been reported in several individuals who underwent genetic testing, but whether they presented with a cardiac phenotype was not specified (e.g. Baruteau_2018, Yang_2022). These reports do not provide unequivocal conclusions about association of the variant with SCN5A-related cardiac conditions. At least one publication reported experimental evidence evaluating an impact on protein function and showed no damaging effect of this variant (Gando_2017). The following publications have been ascertained in the context of this evaluation (PMID: 30059973, 33221895, 28370132, 29247119, 24631775, 36129056). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Five classified the variant as uncertain significance and two classified it as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
|
|
Uncertain significance
(Mar 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiac arrhythmia
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV001349233.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This variant changes 1 nucleotide in exon 28 of the SCN5A gene, creating a premature translation stop signal in the last exon. The mutant transcript … (more)
This variant changes 1 nucleotide in exon 28 of the SCN5A gene, creating a premature translation stop signal in the last exon. The mutant transcript is expected to escape nonsense-mediated decay and be expressed as a protein product containing a disrupted C-terminal region. The C-terminal region has been reported to be critical to sodium channel function (PMID: 16686678, 16798729). However, an experimental functional study has shown that this variant has negligible effects on the protein expression and function (PMID: 28370132). This variant has been reported in an individual affected with Brugada syndrome, who also carried another pathogenic variant in the same gene that could explain the observed phenotype (PMID: 33221895). This variant has also been reported in several young individuals affected with sudden unexplained death (PMID 24631775, 28370132, 29247119) or suspected of having a genetic disorder (PMID: 36007526, 36129056). This variant has been identified in 4/279424 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of SCN5A function is a known mechanism of disease (clinicalgenome.org). 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
(Jan 02, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000952718.5
First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg1944*) in the SCN5A gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Arg1944*) in the SCN5A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 73 amino acid(s) of the SCN5A protein. This variant is present in population databases (rs794728940, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with Brugada syndrome and/or sudden unexplained death (PMID: 24631775, 29247119, 33221895, 36007526). ClinVar contains an entry for this variant (Variation ID: 201596). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant disrupts a region of the SCN5A protein in which other variant(s) (p.Arg2012) have been observed in individuals with SCN5A-related conditions (PMID: 27287068). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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 02, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002648323.3
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.R1944* variant (also known as c.5830C>T), located in coding exon 27 of the SCN5A gene, results from a C to T substitution at nucleotide … (more)
The p.R1944* variant (also known as c.5830C>T), located in coding exon 27 of the SCN5A gene, results from a C to T substitution at nucleotide position 5830. This changes the amino acid from an arginine to a stop codon within coding exon 27. This alteration occurs at the 3' terminus of theSCN5A gene, is not expected to trigger nonsense-mediated mRNAdecay, and only impacts the last 3% of the protein. The exact functional effect of this alteration is unknown. This alteration has been previously reported in a sudden death case, but the infant victim was also heterozygous for a second alteration in SCN5A (p.Q1832E) (Wang D et al. Forensic Sci. Int. 2014;237:90-9). Functional studies indicate that this alteration does not have a significant effect on current density, gating kinetics, or trafficking (Gando I et al. Pacing Clin Electrophysiol. 2017;40:703-712). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
|
|
not provided
(-)
|
no classification provided
Method: phenotyping only
|
SCN5A-Related Disorder
Affected status: yes
Allele origin:
unknown
|
GenomeConnect, ClinGen
Accession: SCV000986790.1
First in ClinVar: Aug 31, 2019 Last updated: Aug 31, 2019 |
Comment:
Variant interpretted as Likely pathogenic and reported on 03/29/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report … (more)
Variant interpretted as Likely pathogenic and reported on 03/29/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Cerebral palsy (present) , Abnormality of coordination (present) , Generalized hypotonia (present) , Anxiety (present) , Depressivity (present) , Increased susceptibility to fractures (present) , … (more)
Cerebral palsy (present) , Abnormality of coordination (present) , Generalized hypotonia (present) , Anxiety (present) , Depressivity (present) , Increased susceptibility to fractures (present) , Abnormality of muscle physiology (present) , Abnormality of muscle morphology (present) , Abnormality of the musculature of the limbs (present) , Arrhythmia (present) , Abnormal EKG (present) , Abnormality of the cardiovascular system (present) , Hypertension (present) (less)
Age: 20-29 years
Sex: female
Method: Sanger Sequencing
Testing laboratory: GeneDx
Date variant was reported to submitter: 2018-03-29
Testing laboratory interpretation: Likely pathogenic
|
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 |
---|---|---|---|---|
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 |
A genome sequencing system for universal newborn screening, diagnosis, and precision medicine for severe genetic diseases. | Kingsmore SF | American journal of human genetics | 2022 | PMID: 36007526 |
Brugada syndrome genetics is associated with phenotype severity. | Ciconte G | European heart journal | 2021 | PMID: 33221895 |
Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population. | Monies D | American journal of human genetics | 2019 | PMID: 31130284 |
SCN5A mutations in 442 neonates and children: genotype-phenotype correlation and identification of higher-risk subgroups. | Baruteau AE | European heart journal | 2018 | PMID: 30059973 |
Applying High-Resolution Variant Classification to Cardiac Arrhythmogenic Gene Testing in a Demographically Diverse Cohort of Sudden Unexplained Deaths. | Lin Y | Circulation. Cardiovascular genetics | 2017 | PMID: 29247119 |
Infant sudden death: Mutations responsible for impaired Nav1.5 channel trafficking and function. | Gando I | Pacing and clinical electrophysiology : PACE | 2017 | PMID: 28370132 |
Electrophysiological characterization of a large set of novel variants in the SCN5A-gene: identification of novel LQTS3 and BrS mutations. | Ortiz-Bonnin B | Pflugers Archiv : European journal of physiology | 2016 | PMID: 27287068 |
Cardiac channelopathy testing in 274 ethnically diverse sudden unexplained deaths. | Wang D | Forensic science international | 2014 | PMID: 24631775 |
A carboxyl-terminal hydrophobic interface is critical to sodium channel function. Relevance to inherited disorders. | Glaaser IW | The Journal of biological chemistry | 2006 | PMID: 16798729 |
Sodium channel inactivation in heart: a novel role of the carboxy-terminal domain. | Kass RS | Journal of cardiovascular electrophysiology | 2006 | PMID: 16686678 |
click to load more click to collapse |
Text-mined citations for rs794728940 ...
HelpRecord last updated May 01, 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.