Submissions for variant NM_001165963.4(SCN1A):c.4762T>C (p.Cys1588Arg) (rs121917919)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188974	SCV000242605	likely pathogenic	not provided	2016-12-21	criteria provided, single submitter	clinical testing	p.Cys1588Arg (TGT>CGT): c.4762 T>C in exon 25 of the SCN1A gene (NM_001165963.1) A C1588R variant that is likely pathogenic has been identified in the SCN1A gene. The C1588R variant has been reported previously as a de novo variant in a patient with Dravet syndrome (Marini et al., 2007). The C1588R variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The C1588R 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. Additionally, this substitution alters a conserved position that is predicted to be within the transmembrane segment S2 of the fourth homologous domain, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense variants in nearby residues (G1586E, V1589G) have been reported in the Human Gene Mutation Database in association with SCN1A-related disorders (Stenson et al., 2014). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae	RCV000636318	SCV000757757	pathogenic	Early infantile epileptic encephalopathy	2018-03-06	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine with arginine at codon 1588 of the SCN1A protein (p.Cys1588Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in individuals affected with epileptic encephalopathies (PMID: 17561957, 25818041). ClinVar contains an entry for this variant (Variation ID: 68552). Loss-of-function variants in SCN1A are known to be pathogenic (PMID: 17347258, 18930999). For these reasons, this variant has been classified as Pathogenic.
UniProtKB/Swiss-Prot	RCV000059426	SCV000090950	not provided	Severe myoclonic epilepsy in infancy		no assertion provided	not provided

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