ClinVar Miner

Submissions for variant NM_001330260.2(SCN8A):c.4850G>A (p.Arg1617Gln) (rs587777721)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000144154 SCV000297794 pathogenic Early infantile epileptic encephalopathy 13 2016-07-14 criteria provided, single submitter research
GeneDx RCV000522954 SCV000616869 pathogenic not provided 2018-02-12 criteria provided, single submitter clinical testing The R1617Q missense variant in the SCN8A gene has been reported multiple times as a de novovariant in patients with seizures and intellectual disability (Rauch et al., 2012; Dyment et al., 2014;Wagnon et al., 2015; Kong et al., 2015; Larsen et al., 2015). Functional studies show that R1617Q results in hyperactivity of the sodium channel (Wagnon et al, 2016). The R1617Q variant is notobserved in large population cohorts (Lek et al., 2016). The R1617Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in someproperties. This substitution occurs at a position that is conserved across species and is predicted to be within the voltage-sensor transmembrane segment S4 of the fourth homologous domain of the SCN8A protein. Therefore, the presence of R1617Q is consistent with the diagnosis of an SCN8A-related disorder in this patient.
Invitae RCV000636307 SCV000757746 pathogenic Early infantile epileptic encephalopathy with suppression bursts 2020-08-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1617 of the SCN8A protein (p.Arg1617Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant is one of the common recurrent variants associated with seizures, and has been reported to be de novo in individuals affected with epileptic encephalopathies (PMID: 23020937, 25046240, 25568300, 25785782, 29588952), including early infantile epileptic encephalopathy (PMID: 24888894, 26029160). ClinVar contains an entry for this variant (Variation ID: 156106). Arg1617 is located in the voltage-responsive S4 transmembrane segment of domain IV, which plays a key role in voltage sensing and undergoes a conformational change when the pore opens. Experimental studies have shown that this missense change impaired the sodium channel transition from open state to inactivated state, and resulting in disrupting the normal process of channel inactivation in cultured cells (PMID: 26900580). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV001266283 SCV001444456 pathogenic Inborn genetic diseases 2019-07-18 criteria provided, single submitter clinical testing
OMIM RCV000144154 SCV000189234 pathogenic Early infantile epileptic encephalopathy 13 2014-07-01 no assertion criteria provided literature only
GeneReviews RCV000144154 SCV000298208 pathogenic Early infantile epileptic encephalopathy 13 2016-02-19 no assertion criteria provided literature only
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678845 SCV000805036 uncertain significance developmental delay with seizures 2017-08-25 no assertion criteria provided clinical testing

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