ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.4168G>A (p.Gly1390Arg) (rs780405533)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000618900 SCV000737596 uncertain significance Cardiovascular phenotype 2016-06-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000183189 SCV000235607 uncertain significance not provided 2017-11-09 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SCN5A gene. The G1391R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant has been identified in several unrelated individuals referred for arrhythmia or cardiomyopathy genetic testing at GeneDx. So far, segregation data is limited or absent due to the lack of clinical information provided and/or insufficient participation by informative family members. The G1391R variant is not observed in at a significant frequency in large population cohorts (Lek et al., 2016). The G1391R 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 in mammals. Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function. However, no missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with SCN5A-related disorders (Stenson et al., 2014).
Invitae RCV000471648 SCV000545023 uncertain significance Brugada syndrome 2016-08-16 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 1391 of the SCN5A protein (p.Gly1391Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs780405533, ExAC <0.01%) but has not been reported in the literature in individuals with a SCN5A-related disease. ClinVar contains an entry for this variant (Variation ID: 201589). This variant identified in the SCN5A gene is located in the transmembrane spanning DIII-S4/S5 region of the resulting protein (PMID: 25348405), but it is unclear how this variant impacts the function of this protein. 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on mRNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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