ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.1654G>T (p.Gly552Trp) (rs3918389)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182981 SCV000235380 uncertain significance not specified 2016-09-12 criteria provided, single submitter clinical testing Although the G552W variant has not been published as a pathogenic variant or as a benign variant to our knowledge, it has previously been identified in one other unrelated individual who underwent genetic testing for arrhythmia. This variant was not observed with any significant frequency in approximately 6,300 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 G552W variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense variants in nearby residues (F543L, A551T) and a different variant affecting the same residue (G552R) have been reported in the Human Gene Mutation Database in association with Brugada syndrome (Stenson et al., 2014), supporting the functional importance of this residue and region of the protein. However, additional evidence is needed to determine whether this variant is pathogenic or benign.
Invitae RCV000464476 SCV000545014 uncertain significance Brugada syndrome 2018-06-15 criteria provided, single submitter clinical testing This sequence change replaces glycine with tryptophan at codon 552 of the SCN5A protein (p.Gly552Trp). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and tryptophan. This variant is present in population databases (rs3918389, ExAC 0.02%). This variant has not been reported in the literature in individuals with SCN5A-related disease. ClinVar contains an entry for this variant (Variation ID: 201458). 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. 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.

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