Submissions for variant NM_000335.5(SCN5A):c.4134CAA[1] (p.Asn1379del)

dbSNP: rs794728922

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV000496602	SCV000588140	likely pathogenic	Brugada syndrome 1	2017-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000618968	SCV000737742	likely pathogenic	Cardiovascular phenotype	2017-12-14	criteria provided, single submitter	clinical testing	The c.4140_4142delCAA variant (also known as p.N1380del) is located in coding exon 22 of the SCN5A gene. This variant results from a deletion of nucleotides CAA at position 4140 to 4142. This results in the in-frame deletion of an asparagine residue at codon 1380. This alteration has been reported in several relatives with varying degrees of cardiac conduction disorder and a family history of sudden death in one family (Yang Z et al. Acta Biochim. Biophys. Sin. (Shanghai). 2017;49(3):270-276). This variant has also been detected in two cardiac arrest survivors (Mellor G et al. Circ Cardiovasc Genet. 2017;10:e001686; Tadros R et al. J Am Coll Cardiol EP. 2017;in press). Functional studies indicate that this alteration causes a dominant negative loss of SCN5A function in mammalian kidney cells (Yang Z et al. Acta Biochim. Biophys. Sin. (Shanghai). 2017;49(3):270-276). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012;7(10):e46688). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae	RCV000183164	SCV001234024	uncertain significance	not provided	2024-01-09	criteria provided, single submitter	clinical testing	This variant, c.4140_4142del, results in the deletion of 1 amino acid(s) of the SCN5A protein (p.Asn1380del), 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 individuals with clinical features of Brugada syndrome (PMID: 28159958, 28341781, 28600387, 29759671, 31737537). ClinVar contains an entry for this variant (Variation ID: 201570). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects SCN5A function (PMID: 28159958). 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.
GeneDx	RCV000183164	SCV000235580	not provided	not provided		no assertion provided	clinical testing	The c.4140_4142delCAA in-frame deletion results in the removal of a highly conserved Asparagine amino acid at position 1380 in the SCN5A gene. Missense variants in this same residue (N1380K) and in nearby residues (V1378M, S1382I) have been reported in association with Brugada syndrome, supporting the functional importance of this residue and this region of the protein. This variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.