ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.5381A>G (p.Tyr1794Cys)
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.5381A>G (p.Tyr1794Cys)
Variation ID: 9375 Accession: VCV000009375.6
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3p22.2 3: 38592479 (GRCh37) [ NCBI UCSC ] 3: 38550988 (GRCh38) [ 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 Feb 14, 2024 Feb 6, 2020 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000335.5:c.5381A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000326.2:p.Tyr1794Cys missense NM_001099404.2:c.5384A>G MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001092874.1:p.Tyr1795Cys missense NM_001099405.2:c.5330A>G NP_001092875.1:p.Tyr1777Cys missense NM_001160160.2:c.5285A>G NP_001153632.1:p.Tyr1762Cys missense NM_001160161.2:c.5222A>G NP_001153633.1:p.Tyr1741Cys missense NM_001354701.2:c.5327A>G NP_001341630.1:p.Tyr1776Cys missense NM_198056.3:c.5384A>G NP_932173.1:p.Tyr1795Cys missense NC_000003.12:g.38550988T>C NC_000003.11:g.38592479T>C NG_008934.1:g.103685A>G LRG_289:g.103685A>G LRG_289t1:c.5384A>G LRG_289p1:p.Tyr1795Cys - Protein change
- Y1795C, Y1794C, Y1762C, Y1777C, Y1741C, Y1776C
- Other names
- -
- Canonical SPDI
- NC_000003.12:38550987:T:C
-
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.
-
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 |
3724 | 4156 |
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. |
---|---|---|---|---|
Pathogenic (1) |
no assertion criteria provided
|
Aug 17, 2001 | RCV000009969.3 | |
not provided (1) |
no classification provided
|
- | RCV000058778.3 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Feb 6, 2020 | RCV001561910.3 | |
Pathogenic (1) |
criteria provided, single submitter
|
Aug 7, 2017 | RCV002345237.1 |
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. |
|
---|---|---|---|---|---|
Pathogenic
(Aug 07, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002641678.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.Y1795C pathogenic mutation (also known as c.5384A>G), located in coding exon 27 of the SCN5A gene, results from an A to G substitution at … (more)
The p.Y1795C pathogenic mutation (also known as c.5384A>G), located in coding exon 27 of the SCN5A gene, results from an A to G substitution at nucleotide position 5384. The tyrosine at codon 1795 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been identified in individuals with long QT syndrome type 3 (LQT3), with segregation reported in multiple families (Rivolta I et al. J. Biol. Chem., 2001 Aug;276:30623-30; Vecchietti S et al. Am. J. Physiol. Heart Circ. Physiol., 2007 Jan;292:H56-65; Benito B et al. Heart Rhythm, 2008 Oct;5:1434-40; Kapa S et al. Circulation, 2009 Nov;120:1752-60; Kilinc OU et al. Congenit Heart Dis 2012 Nov;7:E42-5). In addition, functional studies have demonstrated this alteration leads to slowed inactivation and prolonged depolarization in sodium channels (Rivolta I et al. J. Biol. Chem., 2001 Aug;276:30623-30). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
|
|
Pathogenic
(Feb 06, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001784597.1
First in ClinVar: Aug 14, 2021 Last updated: Aug 14, 2021 |
Comment:
Not observed in large population cohorts (Lek et al., 2016); Reported in ClinVar as pathogenic (ClinVar Variant ID# 9375; Landrum et al., 2016); In silico … (more)
Not observed in large population cohorts (Lek et al., 2016); Reported in ClinVar as pathogenic (ClinVar Variant ID# 9375; Landrum et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Functional studies have shown that Y1795C results in delayed sodium channel inactivation compared to wild type, delaying repolarization and prolonging the QT interval (Rivolta et al., 2001; Clancy et al., 2002; Tateyama et al., 2004; Berecki et al., 2006; Vecchietti et al., 2007); This variant is associated with the following publications: (PMID: 32161207, 28087622, 30361497, 30497731, 28213505, 31257342, 25460862, 24903439, 25904541, 18929331, 12417563, 16254012, 11410597, 24667783, 12084774, 16980337, 14990510, 22129298, 31865383, 19716085) (less)
|
|
Pathogenic
(Mar 03, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000826994.3
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces tyrosine with cysteine at codon 1795 of the SCN5A protein (p.Tyr1795Cys). The tyrosine residue is highly conserved and there is a … (more)
This sequence change replaces tyrosine with cysteine at codon 1795 of the SCN5A protein (p.Tyr1795Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with long QT syndrome in two families (PMID: 11410597, 18929331) and has been reported in an individual with this condition (PMID: 22129298). ClinVar contains an entry for this variant (Variation ID: 9375). Experimental studies have shown that this missense change disrupts SCN5A channel function causing a sustained inward sodium channel current and slowing the onset of inactivation with a prolongation of the action potential (PMID: 11410597, 14990510, 16254012). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Aug 17, 2001)
|
no assertion criteria provided
Method: literature only
|
LONG QT SYNDROME 3
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000030190.2
First in ClinVar: Apr 04, 2013 Last updated: Nov 18, 2016 |
Comment on evidence:
In a patient with long QT syndrome-3 (LQT3; 603830), Rivolta et al. (2001) identified a tyr1795-to-cys (Y1795C) mutation in the SCN5A gene. The mutation slowed … (more)
In a patient with long QT syndrome-3 (LQT3; 603830), Rivolta et al. (2001) identified a tyr1795-to-cys (Y1795C) mutation in the SCN5A gene. The mutation slowed the onset of activation, but did not cause a marked negative shift in the voltage dependence of inactivation or affect the kinetics of the recovery from inactivation. The mutation increased the expression of sustained Na(+) channel activity compared with wildtype channels and promoted entrance into an intermediate or slowly developing inactivated state. (less)
|
|
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: SCV000090298.3
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:11410597;PMID:15840476;PMID:19716085;PMID:19841300;PMID:18929331). 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:11410597;PMID:15840476;PMID:19716085;PMID:19841300;PMID:18929331). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. (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 |
---|---|---|---|---|
Successful elimination of significant arrhythmia burden with flecainide in an adolescent with long QT syndrome type 3. | Kilinc OU | Congenital heart disease | 2012 | PMID: 22129298 |
Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants. | Kapa S | Circulation | 2009 | PMID: 19841300 |
Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test. | Kapplinger JD | Heart rhythm | 2009 | PMID: 19716085 |
A mutation in the sodium channel is responsible for the association of long QT syndrome and familial atrial fibrillation. | Benito B | Heart rhythm | 2008 | PMID: 18929331 |
In silico assessment of Y1795C and Y1795H SCN5A mutations: implication for inherited arrhythmogenic syndromes. | Vecchietti S | American journal of physiology. Heart and circulatory physiology | 2007 | PMID: 16980337 |
Long-QT syndrome-related sodium channel mutations probed by the dynamic action potential clamp technique. | Berecki G | The Journal of physiology | 2006 | PMID: 16254012 |
Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing. | Tester DJ | Heart rhythm | 2005 | PMID: 15840476 |
Structural effects of an LQT-3 mutation on heart Na+ channel gating. | Tateyama M | Biophysical journal | 2004 | PMID: 14990510 |
Inherited Brugada and long QT-3 syndrome mutations of a single residue of the cardiac sodium channel confer distinct channel and clinical phenotypes. | Rivolta I | The Journal of biological chemistry | 2001 | PMID: 11410597 |
Text-mined citations for rs137854614 ...
HelpRecord last updated Apr 20, 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.