ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.310C>T (p.Arg104Trp) (rs199473055)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000434418 SCV000518408 likely pathogenic not provided 2016-12-08 criteria provided, single submitter clinical testing The R104W likely pathogenic variant has been identified in the SCN5A gene. This variant has previously been reported in three unrelated patients with Brugada syndrome (Kapplinger et al., 2010; Clatot et al., 2012). Clatot et al. (2012) identified this variant in a 33 year-old male diagnosed Brugada syndrome type 1 whose father presented with similar ECG abnormalities and died suddenly in his sleep at age 61. The R104W variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R104W 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. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, Clatot et al. (2012) demonstrated that R104W eliminates the sodium current and exerts a dominant-negative effect on the wild type channels. A pathogenic missense variant in the same residue (R104Q) has been reported in HGMD in association with arrhythmia (Stenson et al., 2014), further supporting the functional importance of this residue. However, despite the fact that publications describe an association between the R104W variant in the SCN5A gene and Brugada syndrome, segregation data was not provided.Therefore, this variant is likely pathogenic. In order to definitively determine its clinical significance, additional data is required.
Ambry Genetics RCV000617193 SCV000738139 likely pathogenic Cardiovascular phenotype 2017-09-19 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;Structural Evidence;Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058549 SCV000090069 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;PMID:22739120). 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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