ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.4943G>A (p.Arg1648His) (rs121918622)

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Total submissions: 5
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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.
Invitae RCV001040793 SCV001204383 pathogenic Early infantile epileptic encephalopathy 2019-11-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1648 of the SCN1A protein (p.Arg1648His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with SCN1A-related conditions (PMID: 10742094, 20522430). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12882). This variant has been reported to affect SCN1A protein function (PMID: 12086636, 20100831). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV001192959 SCV001361448 pathogenic Autosomal dominant epilepsy 2019-08-10 criteria provided, single submitter clinical testing Variant summary: SCN1A c.4943G>A (p.Arg1648His) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251356 control chromosomes (gnomAD). c.4943G>A has been published in the literature in multiple affected individuals with varying disease severity, ranging from one reported unaffected individual to several individuals with GEFS+, Dravet syndrome, and related seizure disorder phenotypes (Escayg_2000, Depienne_2009, Depienne_2010, Oates_2018, Snoeijen-Schouwenaars_2019). Most of these patients were reported in a large family, where the variant co-segregated with the disease (Escayg_2000). These data indicate that the variant is very likely to be associated with disease. Publications reported experimental evidence evaluating an impact on protein function, demonstrating mildly reduced channel inactivation resulting in persistent inward sodium current with significantly accelerated recovery (e.g. Spampanato_2004, Alekov_2000, Lossin_2002). In addition, functional studies in mouse models suggested increased excitability of neurons in the central nervous system, resulting in increased seizure susceptibility (e.g. Hedrich_2014, Salgueiro-Pereira_2019). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
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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