ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.2150C>T (p.Pro717Leu) (rs199473149)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058484 SCV000090004 not provided Brugada syndrome no assertion provided literature only This variant has been reported as associated with Brugada syndrome in the following publications (PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Invitae RCV000058484 SCV000760284 uncertain significance Brugada syndrome 2017-09-09 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 717 of the SCN5A protein (p.Pro717Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs199473149, ExAC 0.009%). This variant has been reported in an individual  referred for Brugada syndrome testing (PMID: 20129283). ClinVar contains an entry for this variant (Variation ID: 67717). This variant identified in the SCN5A gene is located in the transmembrane DII-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 and their clinical significance is uncertain. This variant affects a amino acid position that is conserved among other members of the sodium channel family of proteins (PMID: 22581653). Furthermore, a missense substitution at this codon in the SCN1A gene (p.Pro768Leu) has been determined to be pathogenic (PMID: 19350499, 24168886). This suggests that the proline residue is critical for SCN5A protein function and that missense substitutions at this position may also be pathogenic. 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.

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