ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.1333C>G (p.His445Asp) (rs199473112)

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Total submissions: 4
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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 RCV000058414 SCV000089934 not provided Atrial fibrillation no assertion provided literature only This variant has been reported as associated with Atrial fibrillation in the following publications (PMID:18378609). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
GeneDx RCV000418451 SCV000514537 uncertain significance not provided 2018-03-23 criteria provided, single submitter clinical testing The H445D variant in an alternate transcript of the SCN5A gene has been reported in one individual with atrial fibrillation and one individual with a spontaneous Brugada pattern on EKG (Darbar et al., 2008; Le Scouarnec et al., 2015). The variant segregated with disease in two relatives of the proband with atrial fibrillation (Darbar et al., 2008). However, the individual with a spontaneous Brugada pattern additionally harbored a different SCN5A variant. The H445D variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; Exome Variant Server). The H445D variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, this variant is not conserved across species.
Invitae RCV000458775 SCV000545010 uncertain significance Brugada syndrome 2018-09-01 criteria provided, single submitter clinical testing This sequence change replaces histidine with aspartic acid at codon 445 of the SCN5A protein (p.His445Asp). The histidine residue is moderately conserved and there is a moderate physicochemical difference between histidine and aspartic acid. This variant is present in population databases (rs199473112, ExAC 0.02%). This variant has been reported in an individual affected with Brugada syndrome and lone atrial fibrillation (PMID: 25650408, 19808477). It was also shown to segregate with disease in a family affected with atrial fibrillation (PMID: 18378609). ClinVar contains an entry for  this variant (Variation ID: 30046). 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: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). 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.
OMIM RCV000022948 SCV000044239 pathogenic Atrial fibrillation, familial, 10 2008-04-15 no assertion criteria provided literature only

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