ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.3925C>T (p.Leu1309Phe) (rs121918801)

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
GeneDx RCV000188936 SCV000242567 uncertain significance not specified 2013-10-03 criteria provided, single submitter clinical testing The Leu1309Phe missense change has been previously reported in two brothers, one with Dravet syndrome and the other with myoclonic-astatic epilepsy (Dimova et al., 2009). The unaffected mother was negative for the variant; however, the father, who had a history of a single febrile seizure and generalized tonic-clonic seizures, was not tested (Dimova et al., 2009). Leu1309Phe 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. This variant is a conservative amino acid substitution of one uncharged, non-polar amino acid for another. However, the variant alters a conserved position in the S4 subunit of the third transmembrane domain and other missense mutations associated with epilepsy have been reported in this region of the protein. In silico analysis is inconsistent with regard to the effect this variant may have on the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. This variant has been observed to be paternally inheritied. The variant is found in INFANT-EPI panel(s).
Invitae RCV001220193 SCV001392169 likely pathogenic Early infantile epileptic encephalopathy 2019-05-07 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 1309 of the SCN1A protein (p.Leu1309Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with clinical features of epileptic encephalopathy in one family (PMID: 20117752). ClinVar contains an entry for this variant (Variation ID: 68625). 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: "Possibly Damaging"; Align-GVGD: "Class C15"). This variant disrupts the p.Leu1309 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
UniProtKB/Swiss-Prot RCV000059503 SCV000091029 not provided Generalized epilepsy with febrile seizures plus, type 1 no assertion provided not provided

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.