ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.4934G>A (p.Arg1645Gln) (rs121917976)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188986 SCV000242617 pathogenic not provided 2020-07-06 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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; This variant is associated with the following publications: (PMID: 19585586, 17347258, 16713920, 19359143, 19589774, 27864847, 31134136, 31031587)
Neurogenetics Laboratory - MEYER, AOU Meyer RCV000059432 SCV000494514 pathogenic Severe myoclonic epilepsy in infancy 2016-11-16 criteria provided, single submitter clinical testing
Ambry Genetics RCV000720127 SCV000851004 pathogenic History of neurodevelopmental disorder 2016-05-06 criteria provided, single submitter clinical testing The p.R1645Q pathogenic mutation (also known as c.4934G>A), located in coding exon 26 of the SCN1A gene, results from a G to A substitution at nucleotide position 4934. The arginine at codon 1645 is replaced by glutamine, an amino acid with highly similar properties.This alteration has been reported in the literature as de novo in two individuals with theSCN1A-related seizure disorder, Dravet syndrome(Harkin LA, Brain 2007; 130:843-52; Heron SE, J. Med. Genet. 2010; 47(2):137-41;Bolszak M, Epilepsy Res. 2009; 85(2-3):300-4). The position R1645 corresponds to a well-definedarginine (R3)in thevoltage sensing motifknown toplay a significant role in gating function (DeCoursey TE. Physiol Rev.2013;93(2):599-652).Based on the supporting evidence this alterationis interpreted as a disease-causing mutation.
Fulgent Genetics,Fulgent Genetics RCV000763457 SCV000894234 pathogenic Familial hemiplegic migraine type 3; Severe myoclonic epilepsy in infancy; Generalized epilepsy with febrile seizures plus, type 2 2018-10-31 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001198988 SCV001369983 pathogenic Familial hemiplegic migraine type 3 2018-11-28 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PP2,PP3,PS1.
Invitae RCV001208285 SCV001379664 pathogenic Early infantile epileptic encephalopathy with suppression bursts 2020-09-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1645 of the SCN1A protein (p.Arg1645Gln). 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 has been observed in individual(s) with Dravet syndrome (PMID: 17347258, 27864847). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 68558). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
UniProtKB/Swiss-Prot RCV000059432 SCV000090956 not provided Severe myoclonic epilepsy in infancy no assertion provided not provided

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