ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.5726C>T (p.Thr1909Ile) (rs121918793)

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Total submissions: 5
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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

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