ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.940T>C (p.Tyr314His) (rs794728925)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183169 SCV000235585 uncertain significance not provided 2017-11-27 criteria provided, single submitter clinical testing The Tyr314His variant in the SCN5A gene has not been reported previously as a disease-causing mutation nor as a benign polymorphism, to our knowledge. Tyr314His results in a non-conservative substitution of a neutral, polar Tyrosine residue with a positively charged Histidine residue at a position that is conserved across species. Although in silico analysis predicts Tyr314His is probably benign to the protein structure/function (Adzhubei 2010; Schwarz 2011), other mutations affecting nearby residues (Leu315Pro, Lys317Asn) have been reported in association with Brugada syndrome, supporting the functional importance of this region of the protein. The NHLBI ESP Exome Variant Server reports Tyr314His was not observed in approximately 3,000 individuals from European and African American backgrounds. The variant is found in LQT panel(s).
Invitae RCV000196627 SCV000255236 uncertain significance Brugada syndrome 2017-05-14 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with histidine at codon 314 of the SCN5A protein (p.Tyr314His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine. 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: 201574). This variant identified in the SCN5A gene is located in the transmembrane spanning DI-S5/S6 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 is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

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