ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.2677C>T (p.Arg893Cys) (rs199473171)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183009 SCV000235415 uncertain significance not provided 2016-01-20 criteria provided, single submitter clinical testing The R893C mutation in the SCN5A gene has been reported in two unrelated individuals with Brugada syndrome and was not observed in greater than 1300 healthy control subjects (Kapplinger J et al., 2010). Furthermore, the R893C mutation was not observed inapproximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. R893C results in 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. The R893 residue is highly conserved across species. A mutation in the same residue (R893H) and nearby residues (H886P, I890T, F892I, C896S, E901K) have been reported in association with Brugada syndrome, further supporting the functional importance of this region of the protein. In summary, R893C in the SCN5A gene is interpreted as a disease-causing mutation.
Ambry Genetics RCV000619419 SCV000737542 likely pathogenic Cardiovascular phenotype 2019-05-15 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Well-characterized mutation at same position;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues RCV000678939 SCV000805152 likely pathogenic Brugada syndrome 1 2018-03-09 criteria provided, single submitter clinical testing
Invitae RCV000058517 SCV000953030 likely pathogenic Brugada syndrome 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 893 of the SCN5A protein (p.Arg893Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs199473171, ExAC 0.001%). This variant has been observed in individuals affected with Brugada syndrome (PMID: 28341781, Invitae). ClinVar contains an entry for this variant (Variation ID: 67748). 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 disrupts the p.Arg893 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been observed in individuals with SCN5A-related conditions (PMID: 28341781, 23503384, Invitae), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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 RCV000058517 SCV000090037 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.

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