ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.1066G>A (p.Asp356Asn) (rs199473565)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182956 SCV000235353 likely pathogenic not provided 2016-09-01 criteria provided, single submitter clinical testing The D356N likely pathogenic variant was identified in the SCN5A gene. This variant has previously been reported multiple times in association with Brugada syndrome (Makiyama et al., 2005; Hedley et al., 2009; Kapplinger et al., 2010; Kanter et al., 2012; Selga et al., 2015). This variant has also been observed in multiple unrelated individuals referred for cardiac genetic testing at GeneDx; however, segregation data is lacking. The D356N variant was not observed in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.The D356N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species and located within the S5-S6 extracellular loop that constitutes the pore region of NaV1.5 (Kanter et al., 2012). Furthermore, in vitro functional studies have demonstrated that D356N creates a non-functional sodium channel (Makiyama et al., 2005; Shinlapawittayatorn et al., 2011).Therefore, this variant is likely pathogenic based on the evidence currently available.
Integrated Genetics/Laboratory Corporation of America 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
Invitae RCV000058388 SCV000834306 likely pathogenic Brugada syndrome 2018-08-23 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 356 of the SCN5A protein (p.Asp356Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with Brugada syndrome, as well as several individuals referred for Brugada syndrome testing (PMID: 16325048, 26173111, 20129283). ClinVar contains an entry for this variant (Variation ID: 67632). Experimental studies have shown that this missense change results in loss of cardiac sodium channel function (PMID: 16325048, 21840964). 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.
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.

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