Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 463358; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 27535533)
ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.79C>T (p.Arg27Cys)
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.
(9)
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
9
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.79C>T (p.Arg27Cys)
Variation ID: 463358 Accession: VCV000463358.13
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3p22.2 3: 38633229 (GRCh38) [ NCBI UCSC ] 3: 38674720 (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 Oct 10, 2018 Apr 20, 2024 Dec 13, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000335.5:c.79C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000326.2:p.Arg27Cys missense NM_001099404.2:c.79C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001092874.1:p.Arg27Cys missense NM_001099405.2:c.79C>T NP_001092875.1:p.Arg27Cys missense NM_001160160.2:c.79C>T NP_001153632.1:p.Arg27Cys missense NM_001160161.2:c.79C>T NP_001153633.1:p.Arg27Cys missense NM_001354701.2:c.79C>T NP_001341630.1:p.Arg27Cys missense NM_198056.3:c.79C>T NP_932173.1:p.Arg27Cys missense NC_000003.12:g.38633229G>A NC_000003.11:g.38674720G>A NG_008934.1:g.21444C>T LRG_289:g.21444C>T LRG_289t1:c.79C>T LRG_289p1:p.Arg27Cys - Protein change
- R27C
- Other names
- -
- Canonical SPDI
- NC_000003.12:38633228: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.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
The Genome Aggregation Database (gnomAD) 0.00001
- 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 (6) |
criteria provided, multiple submitters, no conflicts
|
Nov 15, 2023 | RCV000786216.10 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 13, 2023 | RCV003591749.3 | |
|
SCN5A-related disorder
|
not provided (1) |
no classification provided
|
- | RCV004545786.1 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Jan 25, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002501194.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
|
|
|
Uncertain significance
(Jul 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002050421.2
First in ClinVar: Jan 08, 2022 Last updated: Mar 04, 2023 |
Comment:
Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (Lek et al., 2016); … (more)
Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 463358; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 27535533) (less)
|
|
|
Uncertain significance
(Nov 21, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiac arrhythmia
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV004362256.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with cysteine at codon 27 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces arginine with cysteine at codon 27 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 an individual affected with hypertrophic cardiomyopathy (PMID: 30847666), in two individuals suspected of having epilepsy, and in another two individuals affected with cardiovascular diseases that were not inherited arrhythmia (PMID: 31696929). This variant has been identified in 4/248756 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
(Nov 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000637205.4
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 27 of the SCN5A protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 27 of the SCN5A protein (p.Arg27Cys). This variant is present in population databases (rs746360906, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. ClinVar contains an entry for this variant (Variation ID: 463358). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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
(Dec 13, 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: SCV004840291.1
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 arginine with cysteine at codon 27 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces arginine with cysteine at codon 27 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 an individual affected with hypertrophic cardiomyopathy (PMID: 30847666), in two individuals suspected of having epilepsy, and in another two individuals affected with cardiovascular diseases that were not inherited arrhythmia (PMID: 31696929). This variant has been identified in 4/248756 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: 1
|
|
|
Uncertain significance
(Nov 01, 2017)
|
no assertion criteria provided
Method: provider interpretation
|
not provided
Affected status: unknown
Allele origin:
germline
|
Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000924944.1
First in ClinVar: Jun 30, 2019 Last updated: Jun 30, 2019 |
Comment:
p.Arg27Cys (c.79C>T) in exon 2 of the SCN5A gene (NM_198056.2; chr3-38674720-G-A) SCICD Classification: variant of uncertain significance, likely benign based on lack of case data … (more)
p.Arg27Cys (c.79C>T) in exon 2 of the SCN5A gene (NM_198056.2; chr3-38674720-G-A) SCICD Classification: variant of uncertain significance, likely benign based on lack of case data and frequency in the general population. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Case data (not including our patient): none available per our searches and lab report. Population data: Highest MAF in South Asian population: 0.003249%. The variant was reported online in 4 of 122888 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. (less)
|
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001979399.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
|
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001978918.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
|
|
|
not provided
(-)
|
no classification provided
Method: phenotyping only
|
None
Affected status: unknown
Allele origin:
unknown
|
GenomeConnect, ClinGen
Accession: SCV002818396.1
First in ClinVar: Jan 07, 2023 Last updated: Jan 07, 2023 |
Comment:
Variant classified as Uncertain significance and reported on 07-02-2021 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the … (more)
Variant classified as Uncertain significance and reported on 07-02-2021 by Lab or 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:
Maternal teratogenic exposure (present) , Abnormality of vision (present) , Abnormality of the nervous system (present) , Seizure (present) , Short attention span (present) , … (more)
Maternal teratogenic exposure (present) , Abnormality of vision (present) , Abnormality of the nervous system (present) , Seizure (present) , Short attention span (present) , Cafe au lait spots, multiple (present) , Abnormal muscle physiology (present) , Cardiac arrhythmia (present) , Abnormal EKG (present) , Abnormality of the cardiovascular system (present) , Asthma (present) , Abnormal pattern of respiration (present) , Abnormal esophagus morphology (present) , Autoimmunity (present) (less)
Indication for testing: Diagnostic
Age: 20-29 years
Sex: female
Method: Exome Sequencing
Testing laboratory: GeneDx
Date variant was reported to submitter: 2021-07-02
Testing laboratory interpretation: Uncertain significance
|
Comment:
Comment:
This missense variant replaces arginine with cysteine at codon 27 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 an individual affected with hypertrophic cardiomyopathy (PMID: 30847666), in two individuals suspected of having epilepsy, and in another two individuals affected with cardiovascular diseases that were not inherited arrhythmia (PMID: 31696929). This variant has been identified in 4/248756 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:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 27 of the SCN5A protein (p.Arg27Cys). This variant is present in population databases (rs746360906, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. ClinVar contains an entry for this variant (Variation ID: 463358). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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 arginine with cysteine at codon 27 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 an individual affected with hypertrophic cardiomyopathy (PMID: 30847666), in two individuals suspected of having epilepsy, and in another two individuals affected with cardiovascular diseases that were not inherited arrhythmia (PMID: 31696929). This variant has been identified in 4/248756 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:
p.Arg27Cys (c.79C>T) in exon 2 of the SCN5A gene (NM_198056.2; chr3-38674720-G-A) SCICD Classification: variant of uncertain significance, likely benign based on lack of case data and frequency in the general population. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Case data (not including our patient): none available per our searches and lab report. Population data: Highest MAF in South Asian population: 0.003249%. The variant was reported online in 4 of 122888 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.
Comment:
Variant classified as Uncertain significance and reported on 07-02-2021 by Lab or 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.
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:
Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 463358; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 27535533)
Comment:
This missense variant replaces arginine with cysteine at codon 27 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 an individual affected with hypertrophic cardiomyopathy (PMID: 30847666), in two individuals suspected of having epilepsy, and in another two individuals affected with cardiovascular diseases that were not inherited arrhythmia (PMID: 31696929). This variant has been identified in 4/248756 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:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 27 of the SCN5A protein (p.Arg27Cys). This variant is present in population databases (rs746360906, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. ClinVar contains an entry for this variant (Variation ID: 463358). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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 arginine with cysteine at codon 27 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 an individual affected with hypertrophic cardiomyopathy (PMID: 30847666), in two individuals suspected of having epilepsy, and in another two individuals affected with cardiovascular diseases that were not inherited arrhythmia (PMID: 31696929). This variant has been identified in 4/248756 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:
p.Arg27Cys (c.79C>T) in exon 2 of the SCN5A gene (NM_198056.2; chr3-38674720-G-A) SCICD Classification: variant of uncertain significance, likely benign based on lack of case data and frequency in the general population. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Case data (not including our patient): none available per our searches and lab report. Population data: Highest MAF in South Asian population: 0.003249%. The variant was reported online in 4 of 122888 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.
Comment:
Variant classified as Uncertain significance and reported on 07-02-2021 by Lab or 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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Variant frequencies of KCNQ1, KCNH2, and SCN5A in a Chinese inherited arrhythmia cohort and other disease cohorts undergoing genetic testing. | Li X | Annals of human genetics | 2020 | PMID: 31696929 |
| Large next-generation sequencing gene panels in genetic heart disease: yield of pathogenic variants and variants of unknown significance. | van Lint FHM | Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation | 2019 | PMID: 30847666 |
Text-mined citations for rs746360906 ...
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.