ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.3282G>T (p.Trp1094Cys)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000335.5(SCN5A):c.3282G>T (p.Trp1094Cys)
Variation ID: 432236 Accession: VCV000432236.6
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3p22.2 3: 38579439 (GRCh38) [ NCBI UCSC ] 3: 38620930 (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 Aug 20, 2017 May 1, 2024 Feb 3, 2022 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000335.5:c.3282G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000326.2:p.Trp1094Cys missense NM_001099404.2:c.3285G>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001092874.1:p.Trp1095Cys missense NM_001099405.2:c.3285G>T NP_001092875.1:p.Trp1095Cys missense NM_001160160.2:c.3282G>T NP_001153632.1:p.Trp1094Cys missense NM_001160161.2:c.3228+1492G>T intron variant NM_001354701.2:c.3282G>T NP_001341630.1:p.Trp1094Cys missense NM_198056.3:c.3285G>T NP_932173.1:p.Trp1095Cys missense NC_000003.12:g.38579439C>A NC_000003.11:g.38620930C>A NG_008934.1:g.75234G>T NG_053884.1:g.1178C>A LRG_289:g.75234G>T LRG_289t1:c.3285G>T LRG_289p1:p.Trp1095Cys - Protein change
- W1094C, W1095C
- Other names
- -
- Canonical SPDI
- NC_000003.12:38579438:C: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) 0.00000
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
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 | |
LOC110121269 | - | - | - | GRCh38 | - | 417 |
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 (2) |
criteria provided, multiple submitters, no conflicts
|
Feb 3, 2022 | RCV000497768.2 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Mar 11, 2020 | RCV002446970.2 |
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
(Jun 19, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000589944.3
First in ClinVar: Aug 20, 2017 Last updated: Aug 20, 2017 |
Comment:
A variant of uncertain significance has been identified in the SCN5A gene. The W1095C variant has been published in one family with LQTS (Itoh et … (more)
A variant of uncertain significance has been identified in the SCN5A gene. The W1095C variant has been published in one family with LQTS (Itoh et al., 2015); however, specific clinical details were not provided. Additionally, this substitution occurs at a position that is not conserved across species and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Nevertheless, this variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The W1095C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. (less)
|
|
Uncertain significance
(Feb 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV003525141.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SCN5A function (PMID: 29574140). In summary, the available evidence … (more)
Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SCN5A function (PMID: 29574140). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 432236). This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 26669661, 29574140). This variant is present in population databases (rs759924541, gnomAD 0.01%). This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 1095 of the SCN5A protein (p.Trp1095Cys). (less)
|
|
Uncertain significance
(Mar 11, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002611512.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.W1095C variant (also known as c.3285G>T), located in coding exon 17 of the SCN5A gene, results from a G to T substitution at nucleotide … (more)
The p.W1095C variant (also known as c.3285G>T), located in coding exon 17 of the SCN5A gene, results from a G to T substitution at nucleotide position 3285. The tryptophan at codon 1095 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was detected in two individuals from one family with long QT syndrome (LQTS) family; however, specific phenotypic information was not provided (Itoh H et al. Eur. J. Hum. Genet., 2016 08;24:1160-6). In addition, this alteration was detected once in a cohort of individuals with brugada syndrome who were symptomatic or had a family history of brugada syndrome, sudden death, syncope, or arrhythmic diseases (Sonoda K et al. Heart Rhythm, 2018 08;15:1179-1188). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
|
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 |
---|---|---|---|---|
Copy number variations of SCN5A in Brugada syndrome. | Sonoda K | Heart rhythm | 2018 | PMID: 29574140 |
Asymmetry of parental origin in long QT syndrome: preferential maternal transmission of KCNQ1 variants linked to channel dysfunction. | Itoh H | European journal of human genetics : EJHG | 2016 | PMID: 26669661 |
Text-mined citations for rs759924541 ...
HelpRecord last updated May 19, 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.