ClinVar Miner

Submissions for variant NM_001040142.2(SCN2A):c.1846A>G (p.Arg616Gly) (rs772896106)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000658405 SCV000780177 uncertain significance not provided 2018-05-31 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SCN2A gene. The R616G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R616G variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The R616G 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 is predicted to be in the cytoplasmic loop between the first and second homologous domains. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV001222393 SCV001394490 uncertain significance Benign familial neonatal-infantile seizures; Early infantile epileptic encephalopathy 11 2019-07-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 616 of the SCN2A protein (p.Arg616Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is present in population databases (rs772896106, ExAC 0.002%). This variant has not been reported in the literature in individuals with SCN2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 546513). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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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