Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000429534 | SCV000515906 | likely pathogenic | not provided | 2023-01-24 | criteria provided, single submitter | clinical testing | Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease; Published functional studies demonstrate a damaging effect as the variant results in the use of a cryptic spice donor site downstream of the natural donor site, leading to a frameshift (O'Neill et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21273195, 33221895, 25525159, 19251209, 20129283, 21321465, 29709101, 29709244, 36197721, 35124229) |
| Labcorp Genetics |
RCV000429534 | SCV001382063 | likely pathogenic | not provided | 2024-01-11 | criteria provided, single submitter | clinical testing | This sequence change falls in intron 25 of the SCN5A gene. It does not directly change the encoded amino acid sequence of the SCN5A protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of SCN5A-related conditions (PMID: 19251209, 21321465, 33221895, 35124229, 36578016; Invitae). ClinVar contains an entry for this variant (Variation ID: 379225). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 36197721). 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. |
| Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, |
RCV001256847 | SCV001433332 | likely pathogenic | Brugada syndrome 1 | 2019-03-11 | criteria provided, single submitter | clinical testing | |
| Roden Lab, |
RCV001256847 | SCV002588735 | likely pathogenic | Brugada syndrome 1 | 2022-10-05 | criteria provided, single submitter | research | The SCN5A variant c.4437+5G>A was observed in 2 cases of Brugada Syndrome and is absent from large population databases (PMID: 32893267). The variant is predicted to alter mRNA splicing. Functional investigations in an iPSC-CM model showed pseudoexon inclusion induced by the edited allele that introduced a frameshift in the predominant aberrantly spliced product. These findings collectively support a Likely Pathogenic classification. |
| Ambry Genetics | RCV002328929 | SCV002631295 | uncertain significance | Cardiovascular phenotype | 2022-01-11 | criteria provided, single submitter | clinical testing | The c.4437+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 24 in the SCN5A gene. This variant has been seen in several Brugada syndrome (BrS) cohorts (Ciconte G et al. Eur Heart J, 2021 03;42:1082-1090; Amin AS et al. Int J Cardiol, 2018 Sep;266:128-132; Nakajima T et al. Int Heart J, 2011;52:27-31; Meregalli PG et al. Heart Rhythm, 2009 Mar;6:341-8). This nucleotide position is highly conserved in available vertebrate species. This alteration is located within a U12-type intron and in silico tools are not reliable predictors of splice sites in this type of intron. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Clinical Genetics Laboratory, |
RCV000429534 | SCV005196826 | uncertain significance | not provided | 2022-05-27 | criteria provided, single submitter | clinical testing | |
| Division of Human Genetics, |
RCV000477868 | SCV000536910 | uncertain significance | Long QT syndrome 3 | 2016-08-23 | no assertion criteria provided | research |