ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.5299A>G (p.Ile1767Val)
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
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NM_000335.5(SCN5A):c.5299A>G (p.Ile1767Val)
Variation ID: 67980 Accession: VCV000067980.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 38551070 (GRCh38) [ NCBI UCSC ] 3: 38592561 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Nov 2, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000335.5:c.5299A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000326.2:p.Ile1767Val missense NM_001099404.2:c.5302A>G MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001092874.1:p.Ile1768Val missense NM_001099405.2:c.5248A>G NP_001092875.1:p.Ile1750Val missense NM_001160160.2:c.5203A>G NP_001153632.1:p.Ile1735Val missense NM_001160161.2:c.5140A>G NP_001153633.1:p.Ile1714Val missense NM_001354701.2:c.5245A>G NP_001341630.1:p.Ile1749Val missense NM_198056.3:c.5302A>G NP_932173.1:p.Ile1768Val missense NC_000003.12:g.38551070T>C NC_000003.11:g.38592561T>C NG_008934.1:g.103603A>G LRG_289:g.103603A>G LRG_289t1:c.5302A>G LRG_289p1:p.Ile1768Val LRG_289t3:c.5302A>G LRG_289p3:p.Ile1768Val Q14524:p.Ile1768Val - Protein change
- I1767V, I1768V, I1714V, I1735V, I1749V, I1750V
- Other names
- p.I1768V:ATT>GTT
- Canonical SPDI
- NC_000003.12:38551069:T:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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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) 0.00001
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 | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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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. |
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SCN5A | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3779 | 4220 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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. |
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not provided (1) |
no classification provided
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- | RCV000058766.3 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 2, 2021 | RCV000183198.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 8, 2016 | RCV000620629.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 1, 2016 | RCV000660252.1 |
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
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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. |
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Pathogenic
(Nov 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome 3
Affected status: yes
Allele origin:
germline
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Center for Human Genetics, Inc, Center for Human Genetics, Inc
Accession: SCV000782270.1
First in ClinVar: Jul 09, 2018 Last updated: Jul 09, 2018 |
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Pathogenic
(Jun 08, 2016)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000737391.5
First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024 |
Comment:
The p.I1768V pathogenic mutation (also known as c.5302A>G), located in coding exon 27 of the SCN5A gene, results from an A to G substitution at … (more)
The p.I1768V pathogenic mutation (also known as c.5302A>G), located in coding exon 27 of the SCN5A gene, results from an A to G substitution at nucleotide position 5302. The isoleucine at codon 1768 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported in a number of individuals diagnosed with long QT Syndrome (LQTS), and was shown to segregate with disease in one family (Rivolta I et al, Physiol. Genomics 2002 Sep; 10(3):191-7; Groenewegen WA et al, Cardiovasc. Res. 2003 Mar; 57(4):1072-8; Chung SK et al, Heart Rhythm 2007 Oct; 4(10):1306-14; Nannenberg EA et al, Circ Cardiovasc Genet 2012 Apr; 5(2):183-9; Kauferstein S et al, Int. J. Legal Med. 2013 Jan; 127(1):145-51). In addition, functional studies revealed that this alteration leads to altered recovery time from channel inactivation state (Rivolta I et al, Physiol. Genomics 2002 Sep; 10(3):191-7; Clancy CE et al, Circulation 2003 May; 107(17):2233-7; Groenewegen WA et al, Cardiovasc. Res. 2003 Mar; 57(4):1072-8; Kauferstein S et al, Int. J. Legal Med. 2013 Jan; 127(1):145-51). Based on the available evidence, p.I1768V is classified as a pathogenic mutation. (less)
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Pathogenic
(Nov 02, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000235616.15
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
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 … (more)
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; Published functional studies demonstrate a damaging effect as this variant results in an increased rate of recovery from the inactive channel state and subsequent channel reopening allowing persistent inward current (Rivolta et al., 2002; Groenewegen et al., 2003; Kauferstein et al., 2013); Reported in ClinVar as pathogenic (ClinVar Variant ID# 67980; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 22581653, 12695286, 18929244, 12650885, 22370996, 12566525, 17905336, 17088455, 25804018, 31737537, 17556201, 12209021, 20513597, 22373669, 19841300) (less)
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Pathogenic
(Apr 05, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000637178.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change increases the rate of channel recovery from … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change increases the rate of channel recovery from activation and decreases the speed of inactivation (PMID: 12209021, 12650885). This variant identified in the SCN5A gene is located in the transmembrane DIV-S6 region of the resulting protein (PMID: 25348405). For more information about the location of this variant, please visit www.invitae.com/SCN5A-topology. This variant has been reported in individuals and families affected with long QT syndrome (PMID: 12566525, 17088455, 17905336, 19841300, 21350584, 22373669). ClinVar contains an entry for this variant (Variation ID: 67980). This variant is not present in population databases (rs199473311, ExAC no frequency). This sequence change replaces isoleucine with valine at codon 1768 of the SCN5A protein (p.Ile1768Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Congenital long QT syndrome
Affected status: unknown
Allele origin:
germline
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Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust
Accession: SCV000090286.3
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:12209021;PMID:12566525;PMID:17905336;PMID:19841300;PMID:22370996;PMID:22373669). 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:12209021;PMID:12566525;PMID:17905336;PMID:19841300;PMID:22370996;PMID:22373669). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. (less)
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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 |
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UniProt: a hub for protein information. | UniProt Consortium | Nucleic acids research | 2015 | PMID: 25348405 |
Cardiac channelopathy causing sudden death as revealed by molecular autopsy. | Kauferstein S | International journal of legal medicine | 2013 | PMID: 22370996 |
Mortality of inherited arrhythmia syndromes: insight into their natural history. | Nannenberg EA | Circulation. Cardiovascular genetics | 2012 | PMID: 22373669 |
Recurrent and Founder Mutations in the Netherlands: the Long-QT Syndrome. | Hofman N | Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation | 2011 | PMID: 21350584 |
Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants. | Kapa S | Circulation | 2009 | PMID: 19841300 |
Long QT and Brugada syndrome gene mutations in New Zealand. | Chung SK | Heart rhythm | 2007 | PMID: 17905336 |
Genotype-specific onset of arrhythmias in congenital long-QT syndrome: possible therapy implications. | Tan HL | Circulation | 2006 | PMID: 17088455 |
Non-equilibrium gating in cardiac Na+ channels: an original mechanism of arrhythmia. | Clancy CE | Circulation | 2003 | PMID: 12695286 |
A novel LQT3 mutation implicates the human cardiac sodium channel domain IVS6 in inactivation kinetics. | Groenewegen WA | Cardiovascular research | 2003 | PMID: 12650885 |
The use of genotype-phenotype correlations in mutation analysis for the long QT syndrome. | Van Langen IM | Journal of medical genetics | 2003 | PMID: 12566525 |
A novel SCN5A mutation associated with long QT-3: altered inactivation kinetics and channel dysfunction. | Rivolta I | Physiological genomics | 2002 | PMID: 12209021 |
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Text-mined citations for rs199473311 ...
HelpRecord last updated Oct 13, 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.