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 2018-05-02 criteria provided, single submitter clinical testing The R1645Q missense variant in the SCN1A gene has been reported previously as a de novo variant in association with Dravet syndrome (also called severe myoclonic epilepsy of infancy or SMEI) (Berkovic et al., 2006; Harkin et al., 2007; Bolszak et al., 2009; Parrini et al., 2017). The R1645Q variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The R1645Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Additionally, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Furthermore, missense variants in nearby residues have been reported in the Human Gene Mutation Database in individuals with SCN1A-related disorders (Stenson et al., 2014). This substitution is predicted to be within the transmembrane segment S4 voltage sensor of the fourth homologous domain. Therefore, the presence of R1645Q is consistent with the diagnosis of an SCN1A-related disorder in this individual.
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 Confirmed de novo alteration in the setting of a new disease (appropriate phenotype) in the family;Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Structural Evidence;Other strong data supporting pathogenic classification
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 Epilepsy 2018-11-28 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PM5,PP3. This variant was detected in heterozygous state.
Invitae RCV001208285 SCV001379664 pathogenic Early infantile epileptic encephalopathy 2019-10-23 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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