ClinVar Miner

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

dbSNP: 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 2021-04-23 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect as this variant 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); Additional 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; Salgueiro-Pereira et al., 2019); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 12086636, 27267376, 10486327, 20522430, 14702334, 20100831, 23311867, 10742094, 25378155, 11118488, 11567038, 28717674, 26410685, 30525188, 33841294, 32090326, 30659983)
Invitae RCV001040793 SCV001204383 pathogenic Early infantile epileptic encephalopathy with suppression bursts 2021-08-27 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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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