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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000030200	OMIM	no assertion criteria provided	Pathogenic (Mar 12, 2002)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 10590249, 11889015

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000030200

OMIM

no assertion criteria provided

Pathogenic
(Mar 12, 2002)

germline

literature only

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature 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

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 5, 2022

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