Submissions for variant NM_000335.5(SCN5A):c.4513C>T (p.Pro1505Ser)

dbSNP: rs2061147191

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	RCV001261991	SCV001439273	likely pathogenic	Brugada syndrome 1	2020-10-27	criteria provided, single submitter	clinical testing	The variant c.4516C>T (p.P1506S) was evaluated according to ACMG criteria. PM2: Absent from controls (or at extremely low frequency if recessive) in the Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium; PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.); PS3: Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. Based on this evidences the c.4516C>T (p.P1506S) variant is classified as Likely Pathogenic.
Invitae	RCV003542338	SCV003525425	uncertain significance	not provided	2022-06-25	criteria provided, single submitter	clinical testing	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. This variant disrupts the p.Pro1506 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been observed in individuals with SCN5A-related conditions (PMID: 23321620, 25626866), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects SCN5A function (PMID: 25626866). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 982413). This missense change has been observed in individual(s) with Brugada syndrome (PMID: 25626866). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1506 of the SCN5A protein (p.Pro1506Ser).
Muscat Medical Center, Bion Medical Genetic Lab	RCV001261991	SCV004034285	pathogenic	Brugada syndrome 1	2014-12-03	criteria provided, single submitter	clinical testing	Here, we present the results of clinical, genetic, and expression studies of a large Iranian family with BrS carrying a novel genetic variant (p.P1506S) inSCN5A. By performing whole-cell patch-clamp experiments using HEK293 cells expressing wild-type (WT) orp.P1506S Nav1.5 channels, hyperpolarizing shift of the availability curve, depolarizing shift of the activation curve, and hastening of the fast inactivation process were observed. These mutant-induced alterations lead to a loss off unction of Nav1.5 and thus suggest that the p.P1506S variant is pathogenic. In addition, cascade familial screening found a family member with BrS who did not carry the p.P1506S mutation.