ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.4916G>C (p.Arg1639Pro) (rs796053029)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188984 SCV000242615 likely pathogenic not provided 2018-05-23 criteria provided, single submitter clinical testing A variant that is likely pathogenic has been identified in the SCN1A gene. The R1639P variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R1639P variant is not observed in large population cohorts (Lek et al., 2016). The R1639P 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 within the transmembrane segment S4 of the fourth homologous domain. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. In addition, missense variants in nearby residues have been reported in the Human Gene Mutation Database in individuals with SCN1A-related disorders (Stenson et al., 2014). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV001244268 SCV001417476 uncertain significance Early infantile epileptic encephalopathy 2019-10-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with proline at codon 1639 of the SCN1A protein (p.Arg1639Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in at least one individual affected with epilepsy and/or neurodevelopmental delay (PMID: 29655203). ClinVar contains an entry for this variant (Variation ID: 206852). 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.