Submissions for variant NM_000335.5(SCN5A):c.3661C>T (p.Leu1221=)

dbSNP: rs1379386304

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001842734	SCV001342904	uncertain significance	Cardiac arrhythmia	2023-05-15	criteria provided, single submitter	clinical testing	This synonymous variant causes a nucleotide substitution but does not change the encoded amino acid at codon 1222 of the SCN5A protein. Splice site prediction tools suggest that this variant may impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with SCN5A-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003669212	SCV004394652	uncertain significance	not provided	2024-08-14	criteria provided, single submitter	clinical testing	This sequence change affects codon 1222 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 not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. ClinVar contains an entry for this variant (Variation ID: 919970). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
All of Us Research Program, National Institutes of Health	RCV001842734	SCV004828272	uncertain significance	Cardiac arrhythmia	2023-05-30	criteria provided, single submitter	clinical testing	This synonymous variant causes a nucleotide substitution but does not change the encoded amino acid at codon 1222 of the SCN5A protein. Splice site prediction tools suggest that this variant may impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with SCN5A-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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.
Roden Lab, Vanderbilt University Medical Center	RCV004698531	SCV005200450	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, 3-38575299-G-A 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 0.3455; 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.