ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.3840+1G>A (rs1366120635)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000578554 SCV000680581 likely pathogenic not provided 2018-01-09 criteria provided, single submitter clinical testing The c.3840+1 G>A likely pathogenic variant in the SCN5A gene has previously been reported multiple times in association with Brugada syndrome (Smits et al., 2002; Nakano et al., 2007; Amin et al., 2009; Hermidia et al., 2010; Kapplinger et al., 2010; Savastano et al., 2014; Selga et al., 2015; Matsumura et al., 2017; Van Malderen et al., 2017; Yamagata et al., 2017). This variant has also been reported in a patient with ARVC with a history of ventricular tachycardia (Erkapic et al., 2008). The c.3840+1 G>A variant destroys the canonical splice donor site in intron 21 and may lead to in-frame skipping of exon 21. This variant may lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. However, in the absence of functional mRNA studies, the physiological consequence of this variant cannot be precisely determined. Nevertheless, other downstream splice site variants in the SCN5A gene have been reported in HGMD in association with arrhythmia (Stenson et al., 2014). Furthermore, the c.3840+1 G>A variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016).
Invitae RCV000688519 SCV000816135 pathogenic Brugada syndrome 2019-06-18 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 21 of the SCN5A gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with Brugada syndrome (PMID: 19843921, 26173111, 29202755, 17404158). This variant has also been reported in an individual with arrhythmogenic right ventricular cardiomyopathy (ARVC) (PMID: 18375968). ClinVar contains an entry for this variant (Variation ID: 488729). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SCN5A are known to be pathogenic (PMID: 20129283, 22789973). For these reasons, this variant has been classified as Pathogenic.

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