ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.2204C>A (p.Ala735Glu) (rs137854611)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000058487 SCV000760197 likely pathogenic Brugada syndrome 2018-01-31 criteria provided, single submitter clinical testing This sequence change replaces alanine with glutamic acid at codon 735 of the SCN5A protein (p.Ala735Glu). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Brugada syndrome (PMID: 11901046, 21321465).   ClinVar contains an entry for this variant (Variation ID: 67720). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). A different missense substitution at this codon (p.Ala735Val) has been determined to be pathogenic (PMID: (PMID: 11823453, 17697823, 20129283, 11823453, 26283144). This suggests that the alanine residue is critical for SCN5A protein function and that other missense substitutions at this position may also be pathogenic. 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 RCV000058487 SCV000090007 not provided Brugada syndrome no assertion provided literature only This variant has been reported as associated with Brugada syndrome in the following publications (PMID:11076825;PMID:11901046). 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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