ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.4516_4524del (p.Gln1506_Pro1508del)
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.4516_4524del (p.Gln1506_Pro1508del)
Variation ID: 201571 Accession: VCV000201571.13
- Type and length
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Deletion, 9 bp
- Location
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Cytogenetic: 3p22.2 3: 38555671-38555679 (GRCh38) [ NCBI UCSC ] 3: 38597162-38597170 (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 May 29, 2016 Feb 20, 2024 Jan 8, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000335.5:c.4516_4524del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000326.2:p.Gln1506_Pro1508del inframe deletion NM_001099404.2:c.4519_4527del MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001092874.1:p.Gln1507_Pro1509del inframe deletion NM_001099405.2:c.4465_4473del NP_001092875.1:p.Gln1489_Pro1491del inframe deletion NM_001160160.2:c.4516_4524del NP_001153632.1:p.Gln1506_Pro1508del inframe deletion NM_001160161.2:c.4357_4365del NP_001153633.1:p.Gln1453_Pro1455del inframe deletion NM_001354701.2:c.4462_4470del NP_001341630.1:p.Gln1488_Pro1490del inframe deletion NM_198056.2:c.4519_4527delCAGAAGCCC inframe deletion NM_198056.3:c.4519_4527del NP_932173.1:p.Gln1507_Pro1509del inframe deletion NC_000003.12:g.38555679_38555687del NC_000003.11:g.38597170_38597178del NG_008934.1:g.98994_99002del LRG_289:g.98994_99002del - Protein change
- Other names
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- Canonical SPDI
- NC_000003.12:38555670:GGGCTTCTGGGGCTTCT:GGGCTTCT
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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
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
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
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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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Pathogenic (1) |
no assertion criteria provided
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Feb 1, 2005 | RCV000009962.6 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 15, 2022 | RCV000183165.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 27, 2020 | RCV002336463.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 8, 2024 | RCV003318368.2 |
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. |
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Pathogenic
(Aug 27, 2020)
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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: SCV002635161.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The c.4519_4527delCAGAAGCCC pathogenic mutation (also known as p.Q1507_P1509del) is located in coding exon 25 of the SCN5A gene. This alteration results from an in-frame deletion … (more)
The c.4519_4527delCAGAAGCCC pathogenic mutation (also known as p.Q1507_P1509del) is located in coding exon 25 of the SCN5A gene. This alteration results from an in-frame deletion of 9 nucleotides at positions 4519 to 4527. This results in the deletion of glutamine-lysine-proline residues at codons 1507 to 1509. This alteration (also known as p.K1505_Q1507del and ΔKPQ) has been described in patients with long QT syndrome in addition to mixed phenotypes including cardiac conduction disease, atrioventricular (AV) block and subsequent development of dilated cardiomyopathy (DCM), and it has been observed to segregate with disease in families (Wang Q et al. Cell, 1995 Mar;80:805-11; Shi R et al. Europace. 2008 Nov;10:1329-35; Asadi M et al. Anatol J Cardiol. 2016 Mar;16:170-4). In functional in vitro analyses, this alteration has adversely affected channel function consistent with gain-of-function effects, resulting in a persistent inward sodium current with a positive shift in steady-state activation potentials and accelerated recovery from inactivation (Keller DI et al. J Mol Cell Cardiol. 2003 Dec;35:1513-21). In addition, mouse models demonstrated that this alteration caused prolonged atrial action potentials, which were reversible with sodium channel blockers (Blana A et al. Heart Rhythm, 2010 Dec;7:1862-9). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jun 15, 2022)
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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: SCV000235581.14
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
Functional studies reported that this in-frame deletion results in a persistent inward sodium current (Bennett et al., 1995; Keller et al., 2003); Deletion of only … (more)
Functional studies reported that this in-frame deletion results in a persistent inward sodium current (Bennett et al., 1995; Keller et al., 2003); Deletion of only the Q1507 residue results in similar functional abnormalities (Keller et al., 2003); Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of three amino acids (Glutamine-Lysine-Proline) in a non-repeat region in the linker region between DIII and DIV in the SCN5A gene (Keller et al., 2003); In silico analysis supports a deleterious effect on protein structure/function; Also known as delKPQ, deltaKPQ, delQKP, or p.Lys1505_Glu1507del (Wang et al., 1995; Tester et al., 2005; Liu et al., 2010; Postema et al., 2011); This variant is associated with the following publications: (PMID: 31535183, 21799153, 24815523, 8917568, 8620612, 20728579, 20102920, 15840476, 26022185, 7889574, 20812931, 28734073, 23098067, 10448858, 30677491, 14654377, 26467377, 18697752, 7651517) (less)
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Pathogenic
(Jan 08, 2024)
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criteria provided, single submitter
Method: research
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Long QT syndrome
Affected status: yes
Allele origin:
paternal
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Dept of Medical Biology, Uskudar University
Accession: SCV004022097.2
First in ClinVar: Jul 29, 2023 Last updated: Jan 26, 2024 |
Comment:
Criteria: PS4_Strong, PS3_Moderate, PM1, PM2, PM4
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: Turkish
Geographic origin: Turkey
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Pathogenic
(May 19, 2022)
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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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Invitae
Accession: SCV000545036.6
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
This variant is also known as delQKP1507‚Äì1509 or delKPQ. ClinVar contains an entry for this variant (Variation ID: 201571). Algorithms developed to predict the effect … (more)
This variant is also known as delQKP1507–1509 or delKPQ. ClinVar contains an entry for this variant (Variation ID: 201571). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects SCN5A function (PMID: 14654377, 18697752, 26022185). For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individuals with clinical features of long QT syndrome (LQTS) (PMID: 18697752, 23098067, 26467377; Invitae). It has also been observed to segregate with disease in related individuals. This variant, c.4519_4527del, results in the deletion of 3 amino acid(s) of the SCN5A protein (p.Gln1507_Pro1509del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). (less)
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Pathogenic
(Feb 01, 2005)
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no assertion criteria provided
Method: literature only
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LONG QT SYNDROME 3
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000030183.4
First in ClinVar: Apr 04, 2013 Last updated: Jan 20, 2017 |
Comment on evidence:
In 2 apparently unrelated kindreds with chromosome 3-linked LQT syndrome (LQT3; 603830), Wang et al. (1995) found deletion of 9 basepairs beginning at nucleotide 4661 … (more)
In 2 apparently unrelated kindreds with chromosome 3-linked LQT syndrome (LQT3; 603830), Wang et al. (1995) found deletion of 9 basepairs beginning at nucleotide 4661 of their cDNA for SCN5A. The deletion, which was detected by sequencing an aberrant SSCP conformer, resulted in deletion of lys-pro-gln (KPQ), which are 3 conserved amino acids in the cytoplasmic linker between domains III and IV of the channel protein. The 3 amino acids involved in the in-frame deletion are lys1505, pro1506, and gln1507. The effect of this mutation on membrane depolarization was studied by Bennett et al. (1995). Clancy and Rudy (1999) developed a model representative of the behavior of the sodium channel in heart muscle cells using a single-channel-based Markov model approach. They showed that the delta-KPQ mutant form of the sodium channel stays open for too long, causing an overlarge inward current of sodium which gives rise to arrhythmia. This model view was corroborated by experiments recording actual sodium currents in cardiac muscle cells. (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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Genetic analysis of cardiac SCN5A Gene in Iranian patients with hereditary cardiac arrhythmias. | Asadi M | Anatolian journal of cardiology | 2016 | PMID: 26467377 |
Intracellular calcium attenuates late current conducted by mutant human cardiac sodium channels. | Potet F | Circulation. Arrhythmia and electrophysiology | 2015 | PMID: 26022185 |
Founder mutations characterise the mutation panorama in 200 Swedish index cases referred for Long QT syndrome genetic testing. | Stattin EL | BMC cardiovascular disorders | 2012 | PMID: 23098067 |
Knock-in gain-of-function sodium channel mutation prolongs atrial action potentials and alters atrial vulnerability. | Blana A | Heart rhythm | 2010 | PMID: 20728579 |
The cardiac sodium channel mutation delQKP 1507-1509 is associated with the expanding phenotypic spectrum of LQT3, conduction disorder, dilated cardiomyopathy, and high incidence of youth sudden death. | Shi R | Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology | 2008 | PMID: 18697752 |
R1193Q of SCN5A, a Brugada and long QT mutation, is a common polymorphism in Han Chinese. | Hwang HW | Journal of medical genetics | 2005 | PMID: 15689442 |
A novel mutation in SCN5A, delQKP 1507-1509, causing long QT syndrome: role of Q1507 residue in sodium channel inactivation. | Keller DI | Journal of molecular and cellular cardiology | 2003 | PMID: 14654377 |
Linking a genetic defect to its cellular phenotype in a cardiac arrhythmia. | Clancy CE | Nature | 1999 | PMID: 10448858 |
SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. | Wang Q | Cell | 1995 | PMID: 7889574 |
Molecular mechanism for an inherited cardiac arrhythmia. | Bennett PB | Nature | 1995 | PMID: 7651517 |
Text-mined citations for rs397514251 ...
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.