_x000D_ Criteria applied: PM5_STR, PS4_MOD, PS3_SUP, PP3
ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.674G>A (p.Arg225Gln)
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.
(11)
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(4); Uncertain significance(6)
Likely pathogenic(4); Uncertain significance(6)
11
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.674G>A (p.Arg225Gln)
Variation ID: 68033 Accession: VCV000068033.25
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3p22.2 3: 38613772 (GRCh38) [ NCBI UCSC ] 3: 38655263 (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 9, 2016 May 1, 2024 Apr 4, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000335.5:c.674G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000326.2:p.Arg225Gln missense NM_001099404.2:c.703+203G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001099405.2:c.703+203G>A intron variant NM_001160160.2:c.703+203G>A intron variant NM_001160161.2:c.703+203G>A intron variant NM_001354701.2:c.703+203G>A intron variant NM_198056.3:c.674G>A NP_932173.1:p.Arg225Gln missense NC_000003.12:g.38613772C>T NC_000003.11:g.38655263C>T NG_008934.1:g.40901G>A LRG_289:g.40901G>A LRG_289t1:c.674G>A LRG_289p1:p.Arg225Gln LRG_289t2:c.674G>A LRG_289p2:p.Arg225Gln Q14524:p.Arg225Gln - Protein change
- R225Q
- Other names
- -
- Canonical SPDI
- NC_000003.12:38613771: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.
-
0.00020 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
Exome Aggregation Consortium (ExAC) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00003
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
- 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 | 4224 | |
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. |
|---|---|---|---|---|
| not provided (1) |
no classification provided
|
- | RCV000058836.11 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Oct 27, 2022 | RCV000812561.13 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 13, 2023 | RCV001842407.13 | |
| Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jun 21, 2022 | RCV001842406.10 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Dec 23, 2021 | RCV004019063.1 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Dec 20, 2017 | RCV000984326.9 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Apr 4, 2024 | RCV000987237.11 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Mar 3, 2023 | RCV001531996.18 |
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
(Dec 20, 2017)
|
criteria provided, single submitter
Method: curation
|
Dilated cardiomyopathy 1E
Affected status: unknown
Allele origin:
germline
|
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Study: CSER_ClinSeq
Accession: SCV001132524.1 First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
Secondary finding: yes
|
|
|
Uncertain significance
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Brugada syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001136487.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
|
|
Likely pathogenic
(Feb 17, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Long QT syndrome 3
Affected status: unknown
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV002102448.1
First in ClinVar: Mar 05, 2022 Last updated: Mar 05, 2022 |
Comment:
_x000D_ Criteria applied: PM5_STR, PS4_MOD, PS3_SUP, PP3
|
|
|
Likely pathogenic
(Jun 21, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Long QT syndrome 3
Affected status: unknown
Allele origin:
germline
|
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn
Accession: SCV002757846.1
First in ClinVar: Dec 03, 2022 Last updated: Dec 03, 2022 |
|
|
|
Uncertain significance
(Dec 23, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV004944536.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
The c.674G>A (p.R225Q) alteration is located in exon 6 (coding exon 5) of the SCN5A gene. This alteration results from a G to A substitution … (more)
The c.674G>A (p.R225Q) alteration is located in exon 6 (coding exon 5) of the SCN5A gene. This alteration results from a G to A substitution at nucleotide position 674, causing the arginine (R) at amino acid position 225 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
|
|
|
Uncertain significance
(Oct 27, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Brugada syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000952879.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 225 of the SCN5A protein (p.Arg225Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 225 of the SCN5A protein (p.Arg225Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with long QT syndrome, Brugada syndrome, dilated cardiomyopathy, or sudden death (PMID: 16922724, 28779003, 29247119, 33071830). ClinVar contains an entry for this variant (Variation ID: 68033). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SCN5A function (PMID: 24815523, 28779003). This variant disrupts the p.Arg225 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12574143, 20031634, 24815523). This suggests that this residue is clinically significant, and that variants that disrupt this residue 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)
|
|
|
Likely pathogenic
(Mar 03, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002099584.4
First in ClinVar: Mar 05, 2022 Last updated: Mar 18, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24815523, 24631775, 29728395, 29247119, 33071830, 16922724, 28779003) (less)
|
|
|
Uncertain significance
(Jun 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiac arrhythmia
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV001342753.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with glutamine at codon 225 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces arginine with glutamine at codon 225 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). Functional studies have shown this variant mildly changes channel activation and channel availability (PMID: 24815523) and decreases peak sodium current density (PMID: 28779003, 35701104). This variant has been reported in individuals affected with Brugada syndrome (PMID: 33071830), long QT syndrome (PMID: 16922724, 32893267), idiopathic dilated cardiomyopathy (PMID: 28779003, 35284542), sudden unexplained death (PMID: 24631775, 29247119), and epilepsy (PMID: 31696929). This variant has been identified in 4/241632 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg225Trp (Clinvar variation ID: 68032) is known to be pathogenic, suggesting that arginine at this position is important for SCN5A protein function. The available clinical 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
(Apr 04, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Brugada syndrome 1
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004809645.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
|
|
|
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: SCV004818075.1
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 glutamine at codon 225 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces arginine with glutamine at codon 225 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). Functional studies have shown this variant mildly changes channel activation and channel availability (PMID: 24815523) and decreases peak sodium current density (PMID: 28779003, 35701104). This variant has been reported in individuals affected with Brugada syndrome (PMID: 33071830), long QT syndrome (PMID: 16922724, 32893267), idiopathic dilated cardiomyopathy (PMID: 28779003, 35284542), sudden unexplained death (PMID: 24631775, 29247119), and epilepsy (PMID: 31696929). This variant has been identified in 4/241632 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg225Trp (Clinvar variation ID: 68032) is known to be pathogenic, suggesting that arginine at this position is important for SCN5A protein function. The available clinical 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: 3
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Congenital long QT syndrome
Affected status: unknown
Allele origin:
germline
|
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust
Accession: SCV000090356.3
First in ClinVar: Oct 22, 2013 Last updated: Oct 09, 2016 |
Comment:
This variant has been reported as associated with Long QT syndrome in the following publications (PMID:16922724). This is a literature report, and does not necessarily … (more)
This variant has been reported as associated with Long QT syndrome in the following publications (PMID:16922724). 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:
The c.674G>A (p.R225Q) alteration is located in exon 6 (coding exon 5) of the SCN5A gene. This alteration results from a G to A substitution at nucleotide position 674, causing the arginine (R) at amino acid position 225 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 225 of the SCN5A protein (p.Arg225Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with long QT syndrome, Brugada syndrome, dilated cardiomyopathy, or sudden death (PMID: 16922724, 28779003, 29247119, 33071830). ClinVar contains an entry for this variant (Variation ID: 68033). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SCN5A function (PMID: 24815523, 28779003). This variant disrupts the p.Arg225 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12574143, 20031634, 24815523). This suggests that this residue is clinically significant, and that variants that disrupt this residue 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.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24815523, 24631775, 29728395, 29247119, 33071830, 16922724, 28779003)
Comment:
This missense variant replaces arginine with glutamine at codon 225 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). Functional studies have shown this variant mildly changes channel activation and channel availability (PMID: 24815523) and decreases peak sodium current density (PMID: 28779003, 35701104). This variant has been reported in individuals affected with Brugada syndrome (PMID: 33071830), long QT syndrome (PMID: 16922724, 32893267), idiopathic dilated cardiomyopathy (PMID: 28779003, 35284542), sudden unexplained death (PMID: 24631775, 29247119), and epilepsy (PMID: 31696929). This variant has been identified in 4/241632 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg225Trp (Clinvar variation ID: 68032) is known to be pathogenic, suggesting that arginine at this position is important for SCN5A protein function. The available clinical 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 missense variant replaces arginine with glutamine at codon 225 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). Functional studies have shown this variant mildly changes channel activation and channel availability (PMID: 24815523) and decreases peak sodium current density (PMID: 28779003, 35701104). This variant has been reported in individuals affected with Brugada syndrome (PMID: 33071830), long QT syndrome (PMID: 16922724, 32893267), idiopathic dilated cardiomyopathy (PMID: 28779003, 35284542), sudden unexplained death (PMID: 24631775, 29247119), and epilepsy (PMID: 31696929). This variant has been identified in 4/241632 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg225Trp (Clinvar variation ID: 68032) is known to be pathogenic, suggesting that arginine at this position is important for SCN5A protein function. The available clinical 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 variant has been reported as associated with Long QT syndrome in the following publications (PMID:16922724). 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:
_x000D_ Criteria applied: PM5_STR, PS4_MOD, PS3_SUP, PP3
Comment:
The c.674G>A (p.R225Q) alteration is located in exon 6 (coding exon 5) of the SCN5A gene. This alteration results from a G to A substitution at nucleotide position 674, causing the arginine (R) at amino acid position 225 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 225 of the SCN5A protein (p.Arg225Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with long QT syndrome, Brugada syndrome, dilated cardiomyopathy, or sudden death (PMID: 16922724, 28779003, 29247119, 33071830). ClinVar contains an entry for this variant (Variation ID: 68033). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SCN5A function (PMID: 24815523, 28779003). This variant disrupts the p.Arg225 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12574143, 20031634, 24815523). This suggests that this residue is clinically significant, and that variants that disrupt this residue 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.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24815523, 24631775, 29728395, 29247119, 33071830, 16922724, 28779003)
Comment:
This missense variant replaces arginine with glutamine at codon 225 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). Functional studies have shown this variant mildly changes channel activation and channel availability (PMID: 24815523) and decreases peak sodium current density (PMID: 28779003, 35701104). This variant has been reported in individuals affected with Brugada syndrome (PMID: 33071830), long QT syndrome (PMID: 16922724, 32893267), idiopathic dilated cardiomyopathy (PMID: 28779003, 35284542), sudden unexplained death (PMID: 24631775, 29247119), and epilepsy (PMID: 31696929). This variant has been identified in 4/241632 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg225Trp (Clinvar variation ID: 68032) is known to be pathogenic, suggesting that arginine at this position is important for SCN5A protein function. The available clinical 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 missense variant replaces arginine with glutamine at codon 225 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). Functional studies have shown this variant mildly changes channel activation and channel availability (PMID: 24815523) and decreases peak sodium current density (PMID: 28779003, 35701104). This variant has been reported in individuals affected with Brugada syndrome (PMID: 33071830), long QT syndrome (PMID: 16922724, 32893267), idiopathic dilated cardiomyopathy (PMID: 28779003, 35284542), sudden unexplained death (PMID: 24631775, 29247119), and epilepsy (PMID: 31696929). This variant has been identified in 4/241632 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg225Trp (Clinvar variation ID: 68032) is known to be pathogenic, suggesting that arginine at this position is important for SCN5A protein function. The available clinical 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 variant has been reported as associated with Long QT syndrome in the following publications (PMID:16922724). 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 |
|---|---|---|---|---|
| Association between SCN5A R225Q variant and dilated cardiomyopathy: potential role of intracellular pH and WNT/β-catenin pathway. | Hu J | Journal of medical genetics | 2022 | PMID: 35701104 |
| Genetic variants in Chinese patients with sporadic dilated cardiomyopathy: a cross-sectional study. | Shen C | Annals of translational medicine | 2022 | PMID: 35284542 |
| 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 |
| Identification of Novel SCN5A Single Nucleotide Variants in Brugada Syndrome: A Territory-Wide Study From Hong Kong. | Tse G | Frontiers in physiology | 2020 | PMID: 33071830 |
| 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 |
| 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 |
| Novel idiopathic DCM-related SCN5A variants localised in DI-S4 predispose electrical disorders by reducing peak sodium current density. | Shen C | Journal of medical genetics | 2017 | PMID: 28779003 |
| Novel SCN5A mutation in amiodarone-responsive multifocal ventricular ectopy-associated cardiomyopathy. | Beckermann TM | Heart rhythm | 2014 | PMID: 24815523 |
| Cardiac channelopathy testing in 274 ethnically diverse sudden unexplained deaths. | Wang D | Forensic science international | 2014 | PMID: 24631775 |
| SCN5A mutations and the role of genetic background in the pathophysiology of Brugada syndrome. | Probst V | Circulation. Cardiovascular genetics | 2009 | PMID: 20031634 |
| Spectrum of pathogenic mutations and associated polymorphisms in a cohort of 44 unrelated patients with long QT syndrome. | Millat G | Clinical genetics | 2006 | PMID: 16922724 |
| Compound heterozygosity for mutations (W156X and R225W) in SCN5A associated with severe cardiac conduction disturbances and degenerative changes in the conduction system. | Bezzina CR | Circulation research | 2003 | PMID: 12574143 |
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Text-mined citations for rs199473071 ...
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 03, 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.