Submissions for variant NM_000335.5(SCN5A):c.393-1C>T

gnomAD frequency: 0.00003  dbSNP: rs759235726

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001195108	SCV000731340	uncertain significance	not specified	2019-06-17	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The c.393-1C>T variant in SCN5A has been reported in1 individual with suspected Brugada syndrome (Nakajima 2011). It has also been identified in 0.009% (2/23002) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant occurs within the canonical splice site (+/- 1,2) which typically cause altered splicing leading to an abnormal or absent protein. However, computational tools do not predict a splicing impact and exon 4 is in-frame, though this information is not predictive enough to rule out pathogenicity. Splice and other loss of function variants in SCN5A are most commonly associated with Brugada syndrome although overlap presentations including other SCN5A-related phenotypes (Long QT syndrome) have been described (Remme 2013). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PVS1_Strong.
Invitae	RCV002223879	SCV000951694	likely pathogenic	not provided	2023-10-06	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 3 of the SCN5A gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individual(s) with Brugada syndrome (PMID: 21321465). ClinVar contains an entry for this variant (Variation ID: 517200). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001841780	SCV001344056	uncertain significance	Cardiac arrhythmia	2023-08-15	criteria provided, single submitter	clinical testing	This variant alters the intron 3 splice acceptor site of the SCN5A gene. This splice acceptor site uses AC, instead of the canonical AG, and is not recognized by computational algorithms that predict potential impact on splicing. To our knowledge, RNA studies have not been reported for this variant. This variant has been reported in an individual affected with Brugada syndrome (PMID: 21321465) and in seven individuals participated in population-based studies whose clinical information was not available (PMID: 30420678, 3142281, 31447099, 32355288). This variant has also been identified in 5/266690 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may disrupt normal splicing and adversely affect protein function, the available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
AiLife Diagnostics, AiLife Diagnostics	RCV002223879	SCV002502984	likely pathogenic	not provided	2020-05-18	criteria provided, single submitter	clinical testing
GeneDx	RCV002223879	SCV002586821	uncertain significance	not provided	2022-10-14	criteria provided, single submitter	clinical testing	Reported in an individual with Brugada syndrome (Nakajima et al., 2011); Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant with an unclear effect on protein function; This variant is associated with the following publications: (PMID: 30662450, 32573973, 31447099, 33087929, 21321465)
Ambry Genetics	RCV002377326	SCV002624305	likely pathogenic	Cardiovascular phenotype	2020-07-23	criteria provided, single submitter	clinical testing	The c.393-1C>T intronic variant results from a C to T substitution one nucleotide upstream from coding exon 3 of the SCN5A gene. This alteration impacts a splice site processed by the U12-spliceosome. Splice sites of U12-introns are not predicted well by in silico tools, but this alteration changes a key nucleotide in the U12 acceptor splice site consensus sequence. As such, this alteration is expected to cause aberrant splicing. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the missing amino acids is unknown, but the impacted region is critical for protein function (Ambry internal data). This variant has been detected in an individual presenting with syncope who had Brugada pattern on ECG with sodium channel blocker challenge, and inducible ventricular fibrillation (Nakajima T et al. Int Heart J, 2011;52:27-31). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.