ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.1100G>A (p.Arg367His) (rs28937318)

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Total submissions: 5
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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 RCV000058390 SCV000089910 not provided Brugada syndrome no assertion provided literature only This variant has been reported as associated with Brugada syndrome in the following publications (PMID:11823453;PMID:14687250;PMID:15028074;PMID:19251209;PMID:22028457;PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues RCV000009988 SCV000611768 pathogenic Brugada syndrome 1 2017-06-28 criteria provided, single submitter clinical testing
Invitae RCV000058390 SCV000545084 pathogenic Brugada syndrome 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 367 of the SCN5A protein (p.Arg367His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (rs28937318, ExAC no frequency). This variant has been reported in several individuals affected with Brugada syndrome (PMID: 17697823, 14753626, 26173111), sudden unexplained nocturnal death syndrome (PMID: 11823453, 24529773), ventricular fibrillation (PMID: 22028457), isolated atrioventricular block (PMID: 22899775), and individuals referred for Brugada testing  (PMID: 20129283). ClinVar contains an entry for this variant (Variation ID: 9390). A different missense substitution at this codon (p.Arg367Cys) has been determined to be pathogenic  (PMID: 21273195, 20129283). This suggests that the arginine residue is critical for SCN5A protein function and that other missense substitutions at this position may also be pathogenic. This variant identified in the SCN5A gene is located in the transmembrane spanning DI-S5/S6 region of the resulting protein (PMID: 25348405). Experimental studies have shown that this missense change causes a complete loss of sodium current (PMID: 11823453, 21840964). In summary, this is a rare variant that has been reported in affected individuals and has been shown to cause a deleterious effect on SCN5A protein function. For these reasons, it has been classified as Pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000058390 SCV000740419 pathogenic Brugada syndrome 2016-11-18 criteria provided, single submitter clinical testing
OMIM RCV000009988 SCV000030209 pathogenic Brugada syndrome 1 2002-02-01 no assertion criteria provided literature only

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