Submissions for variant NM_001165963.4(SCN1A):c.5726C>T (p.Thr1909Ile)

dbSNP: rs121918793

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000494436	SCV000581895	likely pathogenic	not provided	2017-05-01	criteria provided, single submitter	clinical testing	A variant that is likely pathogenic has been identified in the SCN1A gene. The T1909I variant has been previously reported as T1899I (using alternative nomenclature) in an individual with severe myoclonic epilepsy of infancy; parental testing was not reported (Ohmori et al., 2002). Functional studies have demonstrated that T1909I results in a abnormal channel function (Ohmori et al., 2006). The T1909I variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T1909I 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 position predicted to be within the C-terminal cytoplasmic domain. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris	RCV000059549	SCV000586771	pathogenic	Severe myoclonic epilepsy in infancy	2017-01-06	criteria provided, single submitter	clinical testing	Intellectual disability; severe and pharmacoresistant epilepsy (starting with febrile convulsions); pyramidal syndrome; tremor and myoclonus; dysmorphism; scoliosis
Invitae	RCV000705871	SCV000834888	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2022-07-26	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Thr1909 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21248271, 28102150). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1909 of the SCN1A protein (p.Thr1909Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early infantile epileptic encephalopathy and Dravet syndrome (PMID: 12083760, 15277629, 18076640, 28708303). In at least one individual the variant was observed to be de novo. This variant is also known as c.5696C>T (p.Thr1899Ile). ClinVar contains an entry for this variant (Variation ID: 68669). 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. Experimental studies have shown that this missense change affects SCN1A function (PMID: 17054685).
CeGaT Center for Human Genetics Tuebingen	RCV000494436	SCV001245858	pathogenic	not provided	2018-05-01	criteria provided, single submitter	clinical testing
UniProtKB/Swiss-Prot	RCV000059549	SCV000091081	not provided	Severe myoclonic epilepsy in infancy		no assertion provided	not provided