ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.3626T>C (p.Phe1209Ser) (rs794728875)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183040 SCV000235449 likely pathogenic not provided 2013-05-03 criteria provided, single submitter clinical testing The Phe1210Ser variant in the SCN5A gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Phe1210Ser 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. Phe1210Ser results in a non-conservative amino acid substitution of a non-polar, aromatic Phenylalanine with a polar Serine at a position that is conserved across species. Consequently, in silico analysis predicts Phe1210Ser is damaging to the protein structure/function. Mutations in nearby residues (Trp1206Cys, Ser1219Asn) have been reported in association with sudden cardiac death and Brugada syndrome, respectively, further supporting the functional importance of this region of the protein. In summary, Phe1210Ser is a good candidate for a disease-causing mutation. The variant is found in POSTMORTEM panel(s).
Invitae RCV000476501 SCV000545041 uncertain significance Brugada syndrome 2016-12-13 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with serine at codon 1210 of the SCN5A protein (p.Phe1210Ser). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and serine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SCN5A-related disease. ClinVar contains an entry for this variant (Variation ID: 201498). This variant identified in the SCN5A gene is located in the transmembrane DIII-S1 region of the resulting protein (PMID: 25348405). For more information about the location of this variant, please visit www.invitae.com/SCN5A-topology. It is unclear how this variant impacts the function of this protein. 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, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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