NM_000335.5(SCN5A):c.4783T>A (p.Phe1595Ile) AND SCN5A-related disorder

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Apr 27, 2017
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV004528266.1

Allele description [Variation Report for NM_000335.5(SCN5A):c.4783T>A (p.Phe1595Ile)]

NM_000335.5(SCN5A):c.4783T>A (p.Phe1595Ile)

Gene:

SCN5A:sodium voltage-gated channel alpha subunit 5 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000335.5(SCN5A):c.4783T>A (p.Phe1595Ile)

Other names:

p.F1596I:TTC>ATC

HGVS:

NC_000003.12:g.38554306A>T
NG_008934.1:g.100367T>A
NM_000335.5:c.4783T>AMANE SELECT
NM_001099404.2:c.4786T>A
NM_001099405.2:c.4732T>A
NM_001160160.2:c.4714+69T>A
NM_001160161.2:c.4624T>A
NM_001354701.2:c.4729T>A
NM_198056.3:c.4786T>A
NP_000326.2:p.Phe1595Ile
NP_001092874.1:p.Phe1596Ile
NP_001092875.1:p.Phe1578Ile
NP_001153633.1:p.Phe1542Ile
NP_001341630.1:p.Phe1577Ile
NP_932173.1:p.Phe1596Ile
NP_932173.1:p.Phe1596Ile
LRG_289t1:c.4786T>A
LRG_289:g.100367T>A
LRG_289p1:p.Phe1596Ile
NC_000003.11:g.38595797A>T
NM_198056.2:c.4786T>A
Q14524:p.Phe1596Ile

Protein change:

F1542I

Links:

UniProtKB: Q14524#VAR_074751; dbSNP: rs199473278

NCBI 1000 Genomes Browser:

rs199473278

Molecular consequence:

NM_001160160.2:c.4714+69T>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000335.5:c.4783T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.4786T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.4732T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.4624T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.4729T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.4786T>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: SCN5A-related disorder
Identifiers:

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000916018	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Uncertain significance (Apr 27, 2017)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 24606995, 22685113, 25051102, 23838598, 26213684, 19716085 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000916018

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)

Uncertain significance
(Apr 27, 2017)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations in Danish patients with long QT syndrome and the identification of a large founder family with p.F29L in KCNH2.

Christiansen M, Hedley PL, Theilade J, Stoevring B, Leren TP, Eschen O, Sørensen KM, Tybjærg-Hansen A, Ousager LB, Pedersen LN, Frikke-Schmidt R, Aidt FH, Hansen MG, Hansen J, Bloch Thomsen PE, Toft E, Henriksen FL, Bundgaard H, Jensen HK, Kanters JK.

BMC Med Genet. 2014 Mar 7;15:31. doi: 10.1186/1471-2350-15-31.

PubMed [citation]

PMID:: 24606995
PMCID:: PMC4007532

High prevalence of long QT syndrome-associated SCN5A variants in patients with early-onset lone atrial fibrillation.

Olesen MS, Yuan L, Liang B, Holst AG, Nielsen N, Nielsen JB, Hedley PL, Christiansen M, Olesen SP, Haunsø S, Schmitt N, Jespersen T, Svendsen JH.

Circ Cardiovasc Genet. 2012 Aug 1;5(4):450-9. doi: 10.1161/CIRCGENETICS.111.962597. Epub 2012 Jun 8.

PubMed [citation]

PMID:: 22685113

See all PubMed Citations (6)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000916018.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

The SCN5A c.4786T>A (p.Phe1596Ile) missense variant has been reported in five studies of individuals with various cardiac disorders (Kapplinger et al. 2009; Olesen et al. 2012; Christiansen et al. 2014; Boehringer et al. 2014; Hoshi et al. 2015) and described in a heterozygous state in six out of a total of 2814 individuals screened, giving an allele frequency of 0.00178. One of the six individuals also carried two variants in the KCNH2 gene. The variant was also detected in two unaffected individuals in a heterozygous state, one of whom, an unaffected sibling, carried the same additional two variants in the KCNH2 gene as her affected brother (Hoshi et al. 2015). The p.Phe1596Ile variant was absent from 3992 control alleles and is reported at a frequency of 0.00012 in the European (non-Finnish) population of the Exome Aggregation Consortium. The Phe1596 residue is conserved. The variant is described as having no electrophysiological consequence with patch-clamping experiments demonstrating no changes in activation / inactivation parameters or in peak current density compared to wild type (Olesen et al. 2014). Hoshi et al. (2015) confirmed a peak current density similar to wild type with however, a faster recovery from inactivation and increased persistent current compared to wild type. The functional data suggest the p.Phe1596Ile variant has a mild effect, however, due to the prevalence of the variant in cases compared to controls, the p.Phe1596Ile variant is classified as a variant of unknown significance but suspicious for pathogenicity for SCN5A-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

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

Last Updated: Nov 10, 2024

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