ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.4780G>A (p.Asp1594Asn)
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.4780G>A (p.Asp1594Asn)
Variation ID: 9385 Accession: VCV000009385.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 38554309 (GRCh38) [ NCBI UCSC ] 3: 38595800 (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 28, 2024 Dec 28, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000335.5:c.4780G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000326.2:p.Asp1594Asn missense NM_001099404.2:c.4783G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001092874.1:p.Asp1595Asn missense NM_001099405.2:c.4729G>A NP_001092875.1:p.Asp1577Asn missense NM_001160160.2:c.4714+66G>A intron variant NM_001160161.2:c.4621G>A NP_001153633.1:p.Asp1541Asn missense NM_001354701.2:c.4726G>A NP_001341630.1:p.Asp1576Asn missense NM_198056.3:c.4783G>A NP_932173.1:p.Asp1595Asn missense NC_000003.12:g.38554309C>T NC_000003.11:g.38595800C>T NG_008934.1:g.100364G>A LRG_289:g.100364G>A LRG_289t1:c.4783G>A LRG_289p1:p.Asp1595Asn LRG_289t3:c.4783G>A LRG_289p3:p.Asp1595Asn Q14524:p.Asp1595Asn - Protein change
- D1595N, D1594N, D1541N, D1577N, D1576N
- Other names
- p.D1595N:GAC>AAC
- Canonical SPDI
- NC_000003.12:38554308: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
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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
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 |
3724 | 4156 |
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
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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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Jan 22, 2002 | RCV000009983.5 | |
not provided (1) |
no classification provided
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- | RCV000058705.4 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 28, 2023 | RCV000183084.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 28, 2020 | RCV001329632.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jun 5, 2023 | RCV003407312.4 |
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
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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
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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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Likely pathogenic
(Jun 05, 2023)
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criteria provided, single submitter
Method: clinical testing
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SCN5A-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004108243.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The SCN5A c.4783G>A variant is predicted to result in the amino acid substitution p.Asp1595Asn. This variant was reported in an individual with atrioventricular conduction block. … (more)
The SCN5A c.4783G>A variant is predicted to result in the amino acid substitution p.Asp1595Asn. This variant was reported in an individual with atrioventricular conduction block. Furthermore the proband's father and sister had evidence of right bundle-branch block, left axis deviation, and a normal PR interval. Functional studies also support this variant impacts SCN5A function (Wang et al. 2002. PubMed ID: 11804990). A different missense variant impacting the same amino acid residue (p.Asp1595His) has been reported in an individual with dilated cardiomyopathy. Functional studies also support the deleterious nature of the p.Asp1595His variant (Olson et al. 2005. PubMed ID: 15671429; Nguyen et al. 2007. PubMed ID: 18048769). The p.Asp1595Asn variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. (less)
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Pathogenic
(Jan 28, 2020)
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criteria provided, single submitter
Method: clinical testing
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Atrial fibrillation, familial, 10
Affected status: yes
Allele origin:
unknown
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Baylor Genetics
Accession: SCV001521125.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
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Likely pathogenic
(Apr 07, 2023)
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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: SCV000235494.13
First in ClinVar: Jul 05, 2015 Last updated: Apr 15, 2023 |
Comment:
Functional studies of D1595N using a whole-cell patch clamp technique identified a combination of biophysical abnormalities expected to slow myocardial conduction velocity (Wang et al., … (more)
Functional studies of D1595N using a whole-cell patch clamp technique identified a combination of biophysical abnormalities expected to slow myocardial conduction velocity (Wang et al., 2002); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as pathogenic or likely pathogenic (ClinVar Variant ID# 9385; ClinVar); This variant is associated with the following publications: (PMID: 11804990) (less)
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Pathogenic
(Dec 28, 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: SCV000545100.8
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1595 of the SCN5A protein … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1595 of the SCN5A protein (p.Asp1595Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of autosomal dominant SCN5A-related conditions (PMID: 11804990; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9385). 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. Experimental studies have shown that this missense change affects SCN5A function (PMID: 11804990). This variant disrupts the p.Asp1595 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15671429, 18048769). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 22, 2002)
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no assertion criteria provided
Method: literature only
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PROGRESSIVE FAMILIAL HEART BLOCK, TYPE IA
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000030204.3
First in ClinVar: Apr 04, 2013 Last updated: Jan 08, 2018 |
Comment on evidence:
Wang et al. (2002) reported a family in which the proband had presented with first-degree atrioventricular block at the age of 9, progressing to complete … (more)
Wang et al. (2002) reported a family in which the proband had presented with first-degree atrioventricular block at the age of 9, progressing to complete AV block by the age of 20 (PFHB1A; 113900). The proband's sister and father had electrocardiographic evidence of right bundle branch block and left axis deviation with normal PR intervals. The corrected QT interval was normal (less than 420 ms) in all 3 individuals. Sequencing of the coding region of SCN5A revealed a G-to-A mutation at nucleotide position 4783, which replaced an aspartic acid residue at amino acid position 1595 with asparagine (D1595N). The G4783A mutation was engineered into a recombinant human heart sodium channel and transiently coexpressed with human sodium channel beta-1 subunit (600760) in a cultured mammalian cell line (tsA201). Functional characterization using a patch-clamp technique revealed a significant defect in the kinetics of fast-channel inactivation distinct from those of SCN5A mutations reported in LQT3 (603830). The authors considered this a plausible mechanism for the observed conduction system disease in this family. (less)
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not provided
(-)
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no classification provided
Method: literature only
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None
Affected status: unknown
Allele origin:
germline
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Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust
Accession: SCV000090225.3
First in ClinVar: Oct 22, 2013 Last updated: Oct 09, 2016 |
Comment:
This variant has been reported as associated with Atrioventricular conduction block in the following publications (PMID:11804990). This is a literature report, and does not necessarily … (more)
This variant has been reported as associated with Atrioventricular conduction block in the following publications (PMID:11804990). 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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Divergent biophysical defects caused by mutant sodium channels in dilated cardiomyopathy with arrhythmia. | Nguyen TP | Circulation research | 2008 | PMID: 18048769 |
Sodium channel mutations and susceptibility to heart failure and atrial fibrillation. | Olson TM | JAMA | 2005 | PMID: 15671429 |
Clinical, genetic, and biophysical characterization of SCN5A mutations associated with atrioventricular conduction block. | Wang DW | Circulation | 2002 | PMID: 11804990 |
Text-mined citations for rs137854607 ...
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.