Submissions for variant NM_001165963.4(SCN1A):c.5726C>T (p.Thr1909Ile) (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	2018-04-09	criteria provided, single submitter	clinical testing	This sequence change replaces threonine with isoleucine at codon 1909 of the SCN1A protein (p.Thr1909Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals with early infantile epileptic encephalopathy (PMID: 18076640, 12083760, 15277629), and also has been reported to be de novo in an individual affected with Dravet syndrome (PMID: 28708303). This variant is also known as c. 5696C>T (p.Thr1899Ile). ClinVar contains an entry for this variant (Variation ID: 68669). This variant identified in the SCN1A gene is located in the cytoplasmic C-terminal region of the resulting protein (PMID: 25348405, 18804930). Experimental studies have shown that this missense change affecting the normal protein function by decreasing current density and increasing persistent sodium current compared with wild-type SCN1A protein in cells carrying this variant (PMID: 17054685, 21463283). A different variant at this codon (p.Thr1909del) has been determined to be pathogenic (PMID: 21248271,28102150 ). This suggests that the threonine residue is critical for SCN1A protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik 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