Submissions for variant NM_000335.5(SCN5A):c.2422C>T (p.Arg808Cys)

gnomAD frequency: 0.00001  dbSNP: rs749864465

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001841888	SCV000905790	uncertain significance	Cardiac arrhythmia	2019-04-08	criteria provided, single submitter	clinical testing	This missense variant is located in the membrane-spanning segment S4 of the transmembrane domain DII of the SCN5A protein. S4 segment is thought to be a voltage-sensor and contains positively charged amino acids at every third position. This variant changes one of such positively charged amino acids. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed. This variant has been reported in a Greek individual affected with Brugada syndrome (PMID: 19406494). In this family, the proband, brother and paternal first cousin were carriers showing Brugada type 1 ECG, and father with normal ECG was also a carrier. Different variant occurring at the same position, p.Arg808Pro, has been identified in an individual with Brugada syndrome (PMID: 20129283). This variant has been identified in 2/244970 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Invitae	RCV003542312	SCV003525432	likely pathogenic	not provided	2022-03-09	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 628262). This missense change has been observed in individual(s) with Brugada syndrome (PMID: 19406494). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs749864465, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 808 of the SCN5A protein (p.Arg808Cys). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt SCN5A protein function. 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. This variant disrupts the p.Arg808 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been observed in individuals with SCN5A-related conditions (PMID: 30193851), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects SCN5A function (PMID: 32533946).
Institute of Human Genetics, University of Leipzig Medical Center	RCV003322615	SCV004027663	likely pathogenic	Brugada syndrome 1	2023-06-21	criteria provided, single submitter	clinical testing	Criteria applied: PS4_MOD,PM5,PM2_SUP,PP3