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NM_000335.5(SCN5A):c.5382_5384dup (p.Tyr1794_Glu1795insAsp) AND Long QT syndrome 3

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Mar 12, 2002
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000009979.5

Allele description [Variation Report for NM_000335.5(SCN5A):c.5382_5384dup (p.Tyr1794_Glu1795insAsp)]

NM_000335.5(SCN5A):c.5382_5384dup (p.Tyr1794_Glu1795insAsp)

Gene:
SCN5A:sodium voltage-gated channel alpha subunit 5 [Gene - OMIM - HGNC]
Variant type:
Duplication
Cytogenetic location:
3p22.2
Genomic location:
Preferred name:
NM_000335.5(SCN5A):c.5382_5384dup (p.Tyr1794_Glu1795insAsp)
HGVS:
  • NC_000003.12:g.38550986_38550988dup
  • NG_008934.1:g.103686_103688dup
  • NM_000335.5:c.5382_5384dupMANE SELECT
  • NM_001099404.2:c.5385_5387dup
  • NM_001099405.2:c.5331_5333dup
  • NM_001160160.2:c.5286_5288dup
  • NM_001160161.2:c.5223_5225dup
  • NM_001354701.2:c.5328_5330dup
  • NM_198056.3:c.5385_5387dup
  • NP_000326.2:p.Tyr1794_Glu1795insAsp
  • NP_001092874.1:p.Tyr1795_Glu1796insAsp
  • NP_001092875.1:p.Tyr1777_Glu1778insAsp
  • NP_001153632.1:p.Tyr1762_Glu1763insAsp
  • NP_001153633.1:p.Tyr1741_Glu1742insAsp
  • NP_001341630.1:p.Tyr1776_Glu1777insAsp
  • NP_932173.1:p.Glu1796_Ile1797insAsp
  • NP_932173.1:p.Tyr1795_Glu1796insAsp
  • LRG_289t1:c.5385_5387dup
  • LRG_289:g.103686_103688dup
  • LRG_289p1:p.Glu1796_Ile1797insAsp
  • NC_000003.11:g.38592477_38592479dup
  • NM_198056.2:c.5385_5387dup
Links:
OMIM: 600163.0013; dbSNP: rs397514449
NCBI 1000 Genomes Browser:
rs397514449
Molecular consequence:
  • NM_000335.5:c.5382_5384dup - inframe_insertion - [Sequence Ontology: SO:0001821]
  • NM_001099404.2:c.5385_5387dup - inframe_insertion - [Sequence Ontology: SO:0001821]
  • NM_001099405.2:c.5331_5333dup - inframe_insertion - [Sequence Ontology: SO:0001821]
  • NM_001160160.2:c.5286_5288dup - inframe_insertion - [Sequence Ontology: SO:0001821]
  • NM_001160161.2:c.5223_5225dup - inframe_insertion - [Sequence Ontology: SO:0001821]
  • NM_001354701.2:c.5328_5330dup - inframe_insertion - [Sequence Ontology: SO:0001821]
  • NM_198056.3:c.5385_5387dup - inframe_insertion - [Sequence Ontology: SO:0001821]

Condition(s)

Name:
Long QT syndrome 3 (LQT3)
Identifiers:
MONDO: MONDO:0011377; MedGen: C1859062; Orphanet: 101016; Orphanet: 768; OMIM: 603830

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000030200OMIM
no assertion criteria provided
Pathogenic
(Mar 12, 2002) 		germlineliterature only

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only

Citations

PubMed

A single Na(+) channel mutation causing both long-QT and Brugada syndromes.

Bezzina C, Veldkamp MW, van Den Berg MP, Postma AV, Rook MB, Viersma JW, van Langen IM, Tan-Sindhunata G, Bink-Boelkens MT, van Der Hout AH, Mannens MM, Wilde AA.

Circ Res. 1999 Dec 3-17;85(12):1206-13.

PubMed [citation]
PMID:
10590249

Na(+) channel mutation that causes both Brugada and long-QT syndrome phenotypes: a simulation study of mechanism.

Clancy CE, Rudy Y.

Circulation. 2002 Mar 12;105(10):1208-13.

PubMed [citation]
PMID:
11889015
PMCID:
PMC1997279

Details of each submission

From OMIM, SCV000030200.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (2)

Description

In a large Dutch family with electrocardiographic features both of long QT syndrome (LQT3; 603830) and Brugada syndrome (BRGDA1; 601144), Bezzina et al. (1999) demonstrated a 3-bp insertion at nucleotide position 5537 of the SCN5A gene, predicted to cause insertion of an aspartic acid residue at amino acid position 1795 (1795insD) in the C-terminal domain of the protein. Expression of this mutant channel protein in Xenopus oocytes permitted characterization of defects in channel activation and inactivation when compared to a wildtype control. These defects were predicted to cause a reduction in sodium flux during the upstroke of the cardiac action potential.

The co-occurrence of Brugada syndrome and long QT syndrome in this family was paradoxical, since LQT3 is associated with activating SCN5A mutations and Brugada syndrome with inactivating mutations. Clancy and Rudy (2002) modeled the cellular effects of the 1795insD mutation in a virtual transgenic cell. Since ion channel proteins are expressed nonuniformly throughout the myocardium, there is an intrinsic electrophysiologic heterogeneity. The authors demonstrated that the interplay between this underlying myocardial electrophysiologic heterogeneity and the mutation-induced changes in cardiac sodium channel function provided the substrate for both ST segment elevation (in Brugada syndrome) and QT prolongation (LQT3) in a rate-dependent manner.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 5, 2022