Submissions for variant NM_000335.5(SCN5A):c.1066G>A (p.Asp356Asn)

gnomAD frequency: 0.00001  dbSNP: rs199473565

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182956	SCV000235353	likely pathogenic	not provided	2023-03-01	criteria provided, single submitter	clinical testing	Reported multiple times in association with Brugada syndrome in published literature (Makiyama et al., 2005; Hedley et al., 2009; Kapplinger et al., 2010; Kanter et al., 2012; Walsh et al., 2014; Selga et al., 2015; Sonoda et al., 2018; Berthome et al., 2019; Milman et al., 2021); Identified in a patient with sick sinus syndrome (SSS) and hypothyroidism in published literature (Yamane et al., 2022); Identified in a patient with early onset drug-resistant epilepsy who also harbored a de novo pathogenic variant in the SCN1A gene (Tsang et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In vitro functional studies have demonstrated that p.(D356N) creates a non-functional sodium channel (Makiyama et al., 2005; Shinlapawittayatorn et al., 2011); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25863800, 18616619, 19606473, 29574140, 24903439, 22090165, 19027780, 18436145, 26154754, 22885917, 17504259, 21840964, 25904541, 16325048, 26173111, 30662450, 24136861, 30193851, 31737537, 33131149, 20129283, 35650162, 30868116, 22090166, 34461752, 30203441, 32931854)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588086	SCV000700015	pathogenic	Brugada syndrome (shorter-than-normal QT interval)	2017-02-20	criteria provided, single submitter	clinical testing	Variant summary: The SCN5A c.1066G>A (p.Asp356Asn) variant involves the alteration of a conserved nucleotide, is predicted to be damaging by 4/5 in silico tools and is located in Ion transport domain/S5-S6 extracellular loop that constitutes the pore region ((InterPro, Kapplinger_2010, Shinlapawittayatorn_2011). This variant is absent in 123598 control chromosomes from ExAC. This variant has been reported in at least 10 individuals with clinical features of Brugada syndrome and Brugada syndrome plus cardiac conduction defect (Makiyama_2005, Kapplinger_2010, Kanter_2012, Chockalingam_2012, Selga_2015). This variant was found to be one of four recurrent mutations in an international compendium of mutations in the SCN5A in patients referred for Brugada syndrome genetic testing (Kapplinger_2010). In vitro functional assays in HEK293 cells show that this variant leads to defective sodium current (Makiyama_2005, Shinlapawittayatorn_2011). One clinical diagnostic laboratory has classified this variant as likely pathogenic. Missense variants around this region such as p.D349N, p.G351D, p.G351V, p.T353I, p.Y352C, p.R367C, p.R367H, p.R367L, etc. have been reported in patients with BrS and other cardiac diseases, highlighting the functional importance of this region/domian. Taken together, this variant is classified as Pathogenic.
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV000678958	SCV000805174	pathogenic	Brugada syndrome 1	2018-05-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000182956	SCV000834306	pathogenic	not provided	2024-10-03	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 356 of the SCN5A protein (p.Asp356Asn). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with autosomal dominant Brugada syndrome, as well as several individuals referred for Brugada syndrome testing (PMID: 16325048, 20129283, 26173111, 29574140, 30193851, 31737537, 32931854, 33131149). ClinVar contains an entry for this variant (Variation ID: 67632). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SCN5A function (PMID: 16325048, 21840964). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002408568	SCV002717762	likely pathogenic	Cardiovascular phenotype	2024-01-17	criteria provided, single submitter	clinical testing	The p.D356N variant (also known as c.1066G>A), located in coding exon 8 of the SCN5A gene, results from a G to A substitution at nucleotide position 1066. The aspartic acid at codon 356 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in multiple subjects with Brugada syndrome (Makiyama T, J. Am. Coll. Cardiol. 2005 Dec; 46(11):2100-6; Kapplinger JD, Heart Rhythm 2010 Jan; 7(1):33-46; Kanter RJ, Circulation 2012 Jan; 125(1):14-22; Mellor G et al. Circ Cardiovasc Genet, 2017 Jun;10). In addition, in vitro studies have indicated that this alteration has a functional impact on sodium current (Makiyama T, J. Am. Coll. Cardiol. 2005 Dec; 46(11):2100-6; Shinlapawittayatorn K, Circ Cardiovasc Genet 2011 Oct; 4(5):500-9; O'Neill MJ et al. Genet Med. 2022 Jun;24(6):1238-1248). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
All of Us Research Program, National Institutes of Health	RCV000058388	SCV005423976	likely pathogenic	Brugada syndrome	2024-05-14	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 356 in the pore-forming region of the transmembrane domain DI of the SCN5A protein. Functional studies have shown that this variant causes the loss of sodium channel activity (PMID: 16325048, 21840964). This variant has been reported in at least over 10 individuals affected with Brugada syndrome (PMID: 16325048, 24136861, 26173111, 29325976, 32893267, 34649698, 36516610), 8 unrelated individuals suspected of having Brugada syndrome (PMID: 20129283), 1 individual affected with sick sinus syndrome (PMID: 35650162), 2 individuals with other SCN5A-related cardiac symptoms (PMID: 22885917), and one individual affected with drug-resistant epilepsy (PMID: 30868116). This variant has been identified in 1/249040 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058388	SCV000089908	not provided	Brugada syndrome		no assertion provided	literature only	This variant has been reported as associated with Brugada syndrome in the following publications (PMID:16325048;PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.