ClinVar Miner

Submissions for variant NM_006920.6(SCN1A):c.4910G>A (p.Arg1637His) (rs121918622)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000484119 SCV000567083 pathogenic not provided 2018-02-07 criteria provided, single submitter clinical testing The R1648H missense variant in the SCN1A gene has been reported previously in association with Dravet syndrome, GEFS+, and other SCN1A-related disorders (Escayg et al., 2000; Depienne et al., 2010; SCN1A Variant Database). Functional studies indicate that R1684H alters the function of the sodium channel with a defect in channel inactivation (Spampanato et al., 2001; Lossin et al., 2002; Martin et al. 2010). In addition, functional studies in a mouse model demonstrate that R1648H causes an interneuron-specific defect in action potential which causes neuronal network hyperexcitability (Hedrich et al., 2014). The R1648H variant is not observed in large population cohorts (Lek et al., 2016). Although this variant is a conservative amino acid substitution, it is predicted to be within the transmembrane segment S4 of the fourth homologous domain of the SCN1A protein. Additionally, a missense variant at the same position (R1648C) and multiple missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with SCN1A-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Furthermore, in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, R1648H is considered a pathogenic variant.
OMIM RCV000013742 SCV000033989 pathogenic Generalized epilepsy with febrile seizures plus, type 2 2000-04-01 no assertion criteria provided literature only
UniProtKB/Swiss-Prot RCV000059521 SCV000091052 not provided Severe myoclonic epilepsy in infancy no assertion provided not provided

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