ClinVar Miner

Submissions for variant NM_006920.6(SCN1A):c.3743T>C (p.Phe1248Ser) (rs398123591)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000079577 SCV000111459 uncertain significance not provided 2013-09-10 criteria provided, single submitter clinical testing
GeneDx RCV000079577 SCV000242559 likely pathogenic not provided 2018-11-27 criteria provided, single submitter clinical testing A variant that is likely pathogenic has been identified in the SCN1A gene. The F1259S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The F1259S variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The F1259S 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 alters a conserved residue predicted to be within the transmembrane segment S2 of the third homologous domain. In silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense variants at the same residue (F1259C) and in nearby residues (Y1254C, A1255P/D, T1260P, F1263L) have been reported in the Human Gene Mutation Database in association with SCN1A-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV000701047 SCV000829829 uncertain significance Early infantile epileptic encephalopathy 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with serine at codon 1259 of the SCN1A protein (p.Phe1259Ser). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SCN1A-related disease. ClinVar contains an entry for this variant (Variation ID: 93645). 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.