NM_000335.5(SCN5A):c.4716C>T (p.Gly1572=) AND not provided

Clinical significance:Pathogenic (Last evaluated: Jan 7, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000498820.2

Allele description [Variation Report for NM_000335.5(SCN5A):c.4716C>T (p.Gly1572=)]

NM_000335.5(SCN5A):c.4716C>T (p.Gly1572=)

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.4716C>T (p.Gly1572=)
HGVS:
  • NC_000003.12:g.38554373G>A
  • NG_008934.1:g.100300C>T
  • NM_000335.5:c.4716C>TMANE SELECT
  • NM_001099404.2:c.4719C>T
  • NM_001099405.2:c.4665C>T
  • NM_001160160.2:c.4714+2C>T
  • NM_001160161.2:c.4557C>T
  • NM_001354701.2:c.4662C>T
  • NM_198056.3:c.4719C>T
  • NP_000326.2:p.Gly1572=
  • NP_001092874.1:p.Gly1573=
  • NP_001092875.1:p.Gly1555=
  • NP_001153633.1:p.Gly1519=
  • NP_001341630.1:p.Gly1554=
  • NP_932173.1:p.Gly1573=
  • NP_932173.1:p.Gly1573=
  • LRG_289t1:c.4719C>T
  • LRG_289:g.100300C>T
  • LRG_289p1:p.Gly1573=
  • NC_000003.11:g.38595864G>A
  • NM_198056.2:c.4719C>T
Links:
dbSNP: rs754221948
NCBI 1000 Genomes Browser:
rs754221948
Molecular consequence:
  • NM_001160160.2:c.4714+2C>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_000335.5:c.4716C>T - synonymous variant - [Sequence Ontology: SO:0001819]
  • NM_001099404.2:c.4719C>T - synonymous variant - [Sequence Ontology: SO:0001819]
  • NM_001099405.2:c.4665C>T - synonymous variant - [Sequence Ontology: SO:0001819]
  • NM_001160161.2:c.4557C>T - synonymous variant - [Sequence Ontology: SO:0001819]
  • NM_001354701.2:c.4662C>T - synonymous variant - [Sequence Ontology: SO:0001819]
  • NM_198056.3:c.4719C>T - synonymous variant - [Sequence Ontology: SO:0001819]

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000589382GeneDxcriteria provided, single submitter
Pathogenic
(Jan 7, 2019)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From GeneDx, SCV000589382.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The c.4719 C>T pathogenic variant in the SCN5A gene has been reported in association with Brugada syndrome and conduction disease (Amin et al., 2009; Bardai et al., 2013; van der Knijff-van Dortmont, et al., 2016; Roberts et al., 2017). Bardai et al. (2013) reported c.4719 C>T in one patient with a history of ventricular tachycardia during exercise while using nortriptyline. Brugada syndrome was uncovered after ajmaline drug challenge, and the variant was subsequently identified in the patient's affected father. van der Knijff-van Dortmont et al. (2016) reported c.4719 C>T in a patient with first degree heart block and intraventricular conduction delay; the variant was present in the father who also expressed conduction disturbances. Additionally, the c.4719 C>T variant has been reported in a research letter that describes a female patient with a positive ajmaline challenge at 24-years-old (initially negative challenge at 10-years-old), a normal baseline EKG, and a history of syncope (Conte et al., 2014). Most recently, Roberts et al. (2017) reported this variant in a patient with idiopathic bundle branch re-entrant ventricular tachycardia. Although the c.4719 C>T variant results in a synonymous amino acid substitution (G1573=), analysis of SCN5A transcripts from peripheral lymphocytes identified an abnormal splicing product lacking the terminal 96 base pairs of exon 27, corresponding to abnormal splicing at a novel splice site generated by the variant. Furthermore, HEK-293 cells expressing wild-type SCN5A constructs displayed typical inward sodium currents, but no currents were recorded from cells expressing the construct in which the terminal 96 base pairs of exon 27 were deleted (Bardai et al., 2013). Other splice site variants and exonic variants predicted to impact gene splicing have been reported in the SCN5A gene in the Human Gene Mutation Database in association with SCN5A-related disorders (Stenson et al., 2014). Moreover, another splice variant has been reported which uses the same cryptic donor site; mRNA and patch clamp studies demonstrated loss of function with disruption of transmembrane helices S2 and S3 in repeat IV, consistent with Brugada syndrome (Hong et al., 2005). Lastly, the c.4719 C>T variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016).

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

Last Updated: Dec 4, 2021

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