Submissions for variant NM_000335.5(SCN5A):c.4030_4041del (p.Trp1344_Phe1347del)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Roden Lab, Vanderbilt University Medical Center	RCV004698761	SCV005200472	uncertain significance	Brugada syndrome 1		criteria provided, single submitter	research	We classified this variant using data from the calibrated functional assay 'ParSE-seq' (PMID: 37732247), population data, and in silico data within the ACMG v3 framework (PMID: 25741868)The SCN5A variant, 3-38560345-GCTGAAGATGAGC-G was evaluated for association with the loss-of-function condition Brugada Syndrome.This Variant had an AF of 0 in gnomAD v3The in silico predictor SpliceAI scored the variant as 0.5347; normal <0.2, likely damaging >0.5.Using the functional RNA-splicing assay, ParSE-seq, the variant was evaluated to have a strong negative impact on splicing (PS3_strong) following the Brnich et al. calibration framework (PMID: 31892348). In aggregate, we therefore classify this variant as VUS using these collective data.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005103547	SCV005844651	uncertain significance	not provided	2024-12-12	criteria provided, single submitter	clinical testing	This variant, c.4033_4044del, results in the deletion of 4 amino acid(s) of the SCN5A protein (p.Trp1345_Phe1348del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of Brugada syndrome (internal data). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.