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

gnomAD frequency: 0.00001  dbSNP: rs121918801

Total submissions: 4

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	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1309 of the SCN1A protein (p.Leu1309Phe). This variant is present in population databases (rs121918801, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of epileptic encephalopathy (PMID: 20117752). ClinVar contains an entry for this variant (Variation ID: 68625). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SCN1A protein function. 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. For these reasons, this variant has been classified as Pathogenic.
Centogene AG - the Rare Disease Company	RCV001786331	SCV002028345	likely pathogenic	Severe myoclonic epilepsy in infancy	2021-09-01	criteria provided, single submitter	clinical testing
UniProtKB/Swiss-Prot	RCV000059503	SCV000091029	not provided	Generalized epilepsy with febrile seizures plus, type 1		no assertion provided	not provided