ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.4719C>T (p.Gly1573=) (rs754221948)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000253171 SCV000317855 likely pathogenic Cardiovascular phenotype 2012-11-02 criteria provided, single submitter clinical testing
GeneDx RCV000498820 SCV000589382 pathogenic not provided 2019-01-07 criteria provided, single submitter clinical testing 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).
Invitae RCV001037779 SCV001201210 uncertain significance Brugada syndrome 2019-06-27 criteria provided, single submitter clinical testing This sequence change affects codon 1573 of the SCN5A mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the SCN5A protein. This variant is present in population databases (rs754221948, ExAC 0.001%). This variant has been reported in an individual with Brugada syndrome and in a proband and her father, both with conduction disturbances (PMID: 19843921, 27668095). It has also been reported in an individual affected with bundle branch re-entrant ventricular tachycardia (PMID: 29759522). ClinVar contains an entry for this variant (Variation ID: 263423). Experimental studies have shown that this silent change causes a deleterious effect on SCN5A mRNA splicing (PMID: 23425522). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678844 SCV000805035 uncertain significance Cardiac arrhythmia 2016-08-18 no assertion criteria provided clinical testing

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