ClinVar Miner

Submissions for variant NM_001040142.2(SCN2A):c.1613G>A (p.Arg538His) (rs761203730)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189216 SCV000242848 uncertain significance not provided 2013-03-05 criteria provided, single submitter clinical testing The R538H variant in the SCN2A gene has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. R538H results in a conservative amino acid substitution of one positively charged amino acid with another at a residue that is well conserved across species. R538H is located in the intracellular loop between the first and second domains of the SCN2A protein and other missense mutations in this loop have been published in association with SCN2A-related disorders (Herlenius et al., 2007; Shi et al., 2011). In silico analysis was inconsistent with regard to the effect this variant may have on the protein structure/function. We interpret R538H as a variant of unknown significance. The variant is found in EPILEPSY panel(s).
Invitae RCV001052227 SCV001216427 uncertain significance Benign familial neonatal-infantile seizures; Early infantile epileptic encephalopathy 11 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 538 of the SCN2A protein (p.Arg538His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs761203730, ExAC 0.01%). This variant has not been reported in the literature in individuals with SCN2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 207061). 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 tolerated, 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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