ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.4865G>A (p.Arg1622Gln)
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.4865G>A (p.Arg1622Gln)
Variation ID: 9376 Accession: VCV000009376.7
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 38551504 (GRCh38) [ NCBI UCSC ] 3: 38592995 (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 Feb 14, 2024 Apr 25, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000335.5:c.4865G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000326.2:p.Arg1622Gln missense NM_001099404.2:c.4868G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001092874.1:p.Arg1623Gln missense NM_001099405.2:c.4814G>A NP_001092875.1:p.Arg1605Gln missense NM_001160160.2:c.4769G>A NP_001153632.1:p.Arg1590Gln missense NM_001160161.2:c.4706G>A NP_001153633.1:p.Arg1569Gln missense NM_001354701.2:c.4811G>A NP_001341630.1:p.Arg1604Gln missense NM_198056.3:c.4868G>A NP_932173.1:p.Arg1623Gln missense NC_000003.12:g.38551504C>T NC_000003.11:g.38592995C>T NG_008934.1:g.103169G>A LRG_289:g.103169G>A LRG_289t1:c.4868G>A LRG_289p1:p.Arg1623Gln - Protein change
- R1623Q, R1622Q, R1569Q, R1604Q, R1605Q, R1590Q
- Other names
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- Canonical SPDI
- NC_000003.12:38551503:C:T
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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.
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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
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. |
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SCN5A | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3555 | 3959 |
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. |
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Pathogenic (1) |
no assertion criteria provided
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Sep 1, 2006 | RCV000009970.5 | |
Pathogenic (1) |
no assertion criteria provided
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Sep 1, 2006 | RCV000009971.3 | |
not provided (1) |
no classification provided
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- | RCV000058716.3 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Apr 25, 2023 | RCV001588806.4 |
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
(Sep 24, 2019)
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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: SCV001814368.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
Published functional studies using whole cell and/or single channel current analysis show that R1623Q causes a significantly slower inactivation rate of the sodium ion channel, … (more)
Published functional studies using whole cell and/or single channel current analysis show that R1623Q causes a significantly slower inactivation rate of the sodium ion channel, and leads to prolonged opening of the sodium ion channel (Makita et al., 1998; Kambouris et al., 1998); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar as pathogenic (ClinVar Variant ID# 9376; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 32383558, 15670972, 25554238, 15184283, 19716085, 12574983, 9506831, 16922724, 24218437, 9495298, 10200053, 19167409, 24136861, 10772658, 20090423) (less)
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Pathogenic
(Apr 25, 2023)
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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: SCV000960945.3
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SCN5A function (PMID: 9495298, 9506831, 10618304, … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SCN5A function (PMID: 9495298, 9506831, 10618304, 10772658, 15621041, 19167409, 20090423). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 9376). This missense change has been observed in individual(s) with long QT syndrome and severe cardiac outcomes (PMID: 10200053, 10508990, 15051636, 15184283, 15670972, 19841300, 19863579, 20129283, 22360817, 24218437, 25904541). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1623 of the SCN5A protein (p.Arg1623Gln). (less)
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Pathogenic
(Sep 01, 2006)
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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: SCV000030191.2
First in ClinVar: Apr 04, 2013 Last updated: Nov 18, 2016 |
Comment on evidence:
In an infant Japanese girl with a severe form of long QT syndrome (LQT3; 603830), Makita et al. (1998) identified a de novo missense mutation, … (more)
In an infant Japanese girl with a severe form of long QT syndrome (LQT3; 603830), Makita et al. (1998) identified a de novo missense mutation, arg1623 to gln (R1623Q), in the S4 segment of domain 4 of the SCN5A gene. When expressed in oocytes, mutant sodium channels exhibited only minor abnormalities in channel activation, but in contrast to 3 previously characterized LQT3 mutations, had significantly delayed macroscopic inactivation. Single channel analysis revealed that R1623Q channels had significantly prolonged open times with bursting behavior, suggesting a novel mechanism of pathophysiology in Na(+) channel-linked long QT syndrome. Kambouris et al. (2000) reported that the R1623Q mutation imparts unusual lidocaine sensitivity to the sodium channel that is attributable to its altered functional behavior. Studies of lidocaine on individual R1623Q single-channel openings indicated that the open-time distribution was not changed, indicating the drug does not block the open pore as proposed previously. Rather, the mutant channels have a propensity to inactivate without ever opening ('closed-state inactivation'), and lidocaine augments this gating behavior. An allosteric gating model incorporating closed-state inactivation recapitulated the effects of lidocaine on the pathologic sodium current. These findings explained the unusual drug sensitivity of R1623Q and provided a general and unanticipated mechanism for understanding how sodium channel-blocking agents may suppress the pathologic, sustained sodium current induced by LQT3 mutations. In a male infant diagnosed with ventricular arrhythmias and cardiac decompensation in utero at 28 weeks' gestation and with long QT syndrome at birth, Miller et al. (2004) identified heterozygosity for the R1623Q mutation. The mother had no ECG abnormalities, but a previous and a subsequent pregnancy both ended in stillbirth at 7 months. Initial studies detected no genetic abnormality, but a sensitive restriction enzyme-based assay revealed a small percentage (8 to 10%) of cells harboring the mutation in the mother's blood, skin, and buccal mucosa; R1623Q was also identified in cord blood from the third fetus. Miller et al. (2004) concluded that recurrent late-term fetal loss or sudden infant death can result from unsuspected parental mosaicism for LQT-associated mutations. In a 1-month-old male infant who had syncope, torsade de pointes, cardiac arrest, and a QTc of 460 ms, Millat et al. (2006) identified biallelic digenic mutations: a 4868G-A transition in exon 28 of the SCN5A gene resulting in the R1623Q substitution; and a missense mutation in the KCNE2 gene (F60L; 603796.0005). (less)
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Pathogenic
(Sep 01, 2006)
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no assertion criteria provided
Method: literature only
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LONG QT SYNDROME 3/6, DIGENIC
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000030192.2
First in ClinVar: Apr 04, 2013 Last updated: Nov 14, 2016 |
Comment on evidence:
In an infant Japanese girl with a severe form of long QT syndrome (LQT3; 603830), Makita et al. (1998) identified a de novo missense mutation, … (more)
In an infant Japanese girl with a severe form of long QT syndrome (LQT3; 603830), Makita et al. (1998) identified a de novo missense mutation, arg1623 to gln (R1623Q), in the S4 segment of domain 4 of the SCN5A gene. When expressed in oocytes, mutant sodium channels exhibited only minor abnormalities in channel activation, but in contrast to 3 previously characterized LQT3 mutations, had significantly delayed macroscopic inactivation. Single channel analysis revealed that R1623Q channels had significantly prolonged open times with bursting behavior, suggesting a novel mechanism of pathophysiology in Na(+) channel-linked long QT syndrome. Kambouris et al. (2000) reported that the R1623Q mutation imparts unusual lidocaine sensitivity to the sodium channel that is attributable to its altered functional behavior. Studies of lidocaine on individual R1623Q single-channel openings indicated that the open-time distribution was not changed, indicating the drug does not block the open pore as proposed previously. Rather, the mutant channels have a propensity to inactivate without ever opening ('closed-state inactivation'), and lidocaine augments this gating behavior. An allosteric gating model incorporating closed-state inactivation recapitulated the effects of lidocaine on the pathologic sodium current. These findings explained the unusual drug sensitivity of R1623Q and provided a general and unanticipated mechanism for understanding how sodium channel-blocking agents may suppress the pathologic, sustained sodium current induced by LQT3 mutations. In a male infant diagnosed with ventricular arrhythmias and cardiac decompensation in utero at 28 weeks' gestation and with long QT syndrome at birth, Miller et al. (2004) identified heterozygosity for the R1623Q mutation. The mother had no ECG abnormalities, but a previous and a subsequent pregnancy both ended in stillbirth at 7 months. Initial studies detected no genetic abnormality, but a sensitive restriction enzyme-based assay revealed a small percentage (8 to 10%) of cells harboring the mutation in the mother's blood, skin, and buccal mucosa; R1623Q was also identified in cord blood from the third fetus. Miller et al. (2004) concluded that recurrent late-term fetal loss or sudden infant death can result from unsuspected parental mosaicism for LQT-associated mutations. In a 1-month-old male infant who had syncope, torsade de pointes, cardiac arrest, and a QTc of 460 ms, Millat et al. (2006) identified biallelic digenic mutations: a 4868G-A transition in exon 28 of the SCN5A gene resulting in the R1623Q substitution; and a missense mutation in the KCNE2 gene (F60L; 603796.0005). (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: SCV000090236.3
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:9495298;PMID:9506831;PMID:10973849;PMID:12574983;PMID:15051636;PMID:15184283;PMID:16922724;PMID:19167409;PMID:19716085;PMID:19841300;PMID:20090423;PMID:10772658). 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:9495298;PMID:9506831;PMID:10973849;PMID:12574983;PMID:15051636;PMID:15184283;PMID:16922724;PMID:19167409;PMID:19716085;PMID:19841300;PMID:20090423;PMID:10772658). 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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Enhanced Classification of Brugada Syndrome-Associated and Long-QT Syndrome-Associated Genetic Variants in the SCN5A-Encoded Na(v)1.5 Cardiac Sodium Channel. | Kapplinger JD | Circulation. Cardiovascular genetics | 2015 | PMID: 25904541 |
In utero diagnosis of long QT syndrome by magnetocardiography. | Cuneo BF | Circulation | 2013 | PMID: 24218437 |
Congenital long QT 3 in the pediatric population. | Blaufox AD | The American journal of cardiology | 2012 | PMID: 22360817 |
An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing. | Kapplinger JD | Heart rhythm | 2010 | PMID: 20129283 |
Impaired stretch modulation in potentially lethal cardiac sodium channel mutants. | Banderali U | Channels (Austin, Tex.) | 2010 | PMID: 20090423 |
Neonatal seizures and long QT syndrome: a cardiocerebral channelopathy? | Heron SE | Epilepsia | 2010 | PMID: 19863579 |
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 |
Differential modulation of late sodium current by protein kinase A in R1623Q mutant of LQT3. | Tsurugi T | Life sciences | 2009 | PMID: 19167409 |
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 |
Efficacy of an implantable cardioverter-defibrillator in a neonate with LQT3 associated arrhythmias. | Ten Harkel AD | 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 | 2005 | PMID: 15670972 |
Intrinsic mechanism of the enhanced rate-dependent QT shortening in the R1623Q mutant of the LQT3 syndrome. | Oginosawa Y | Cardiovascular research | 2005 | PMID: 15621041 |
Recurrent third-trimester fetal loss and maternal mosaicism for long-QT syndrome. | Miller TE | Circulation | 2004 | PMID: 15184283 |
Compound mutations: a common cause of severe long-QT syndrome. | Westenskow P | Circulation | 2004 | PMID: 15051636 |
Congenital long QT syndrome and 2:1 atrioventricular block with a mutation of the SCN5A gene. | Miura M | Pediatric cardiology | 2003 | PMID: 12574983 |
Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. | Splawski I | Circulation | 2000 | PMID: 10973849 |
A revised view of cardiac sodium channel "blockade" in the long-QT syndrome. | Kambouris NG | The Journal of clinical investigation | 2000 | PMID: 10772658 |
Cardiac Na(+) channel dysfunction in Brugada syndrome is aggravated by beta(1)-subunit. | Makita N | Circulation | 2000 | PMID: 10618304 |
Sodium channel abnormalities are infrequent in patients with long QT syndrome: identification of two novel SCN5A mutations. | Wattanasirichaigoon D | American journal of medical genetics | 1999 | PMID: 10508990 |
A de novo missense mutation (R1623Q) of the SCN5A gene in a Japanese girl with sporadic long QT sydrome. Mutations in brief no. 140. Online. | Yamagishi H | Human mutation | 1998 | PMID: 10200053 |
A de novo missense mutation of human cardiac Na+ channel exhibiting novel molecular mechanisms of long QT syndrome. | Makita N | FEBS letters | 1998 | PMID: 9506831 |
Phenotypic characterization of a novel long-QT syndrome mutation (R1623Q) in the cardiac sodium channel. | Kambouris NG | Circulation | 1998 | PMID: 9495298 |
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Text-mined citations for rs137854600 ...
HelpRecord last updated Mar 23, 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.