ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.311G>A (p.Arg104Gln) (rs199473554)

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Total submissions: 3
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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 RCV000058551 SCV000090071 not provided Brugada syndrome no assertion provided literature only This variant has been reported as associated with Brugada syndrome in the following publications (PMID:11960580;PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
GeneDx RCV000182924 SCV000235319 pathogenic not provided 2017-11-29 criteria provided, single submitter clinical testing p.Arg104Gln (R104Q) CGG>CAG: c.311 G>A in exon 3 of the SCN5A gene (NM_198056.2) The R104Q mutation in the SCN5A gene has been reported in one Moroccan individual with Brugada syndrome who had a family history of Brugada syndrome in two siblings (Levy-Nissenbaum E et al., 2001). Furthermore, in vitro studies in a mammalian expression system showed that R104Q did not result in a functional sodium channel (Gutter C et al., 2013). R104Q is a non-conservative amino acid substitution as these residues differ in polarity, charge, size and/or other properties and is more likely to impact secondary structure. The R104 residue is highly conserved across species (Levy-Nissenbaum E et al., 2001). Mutations in the same residue (R104G, R104W) and in nearby residues (V95I, N109K) have been reported in association with arrhythmia, further supporting the functional importance of this residue and this region of the protein. Additionally, the R104Q mutation was not observed in approximately 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. The variant is found in CARDIOMYOPATHY panel(s).
Invitae RCV000058551 SCV000291795 pathogenic Brugada syndrome 2016-05-22 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 104 of the SCN5A protein (p.Arg104Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple individuals affected with Brugada syndrome (PMID: 11960580, 24136861, 23321620, 20129283, 19716085). ClinVar contains an entry for this variant (Variation ID: 67780). Experimental studies have shown that this missense change in a mammalian cell system did not result in functional proteins and when expressed in Xenopus oocytes functional expression was lower with a significantly reduced peak current amplitude and slowed recovery from inactivation (PMID: 20486126). A different missense substitution at this codon (p.Arg104Trp) is reported to be deleterious (PMID: 24136861, 20129283, 22739120). This indicates that the Arginine residue is important for SCN5A protein function. For these reasons, this variant has been classified as Pathogenic.

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