ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.4786C>T (p.Arg1596Cys) (rs121917993)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188978 SCV000242609 pathogenic not provided 2018-09-19 criteria provided, single submitter clinical testing The R1596C missense variant in the SCN1A gene has been reported previously as a de novo pathogenic variant in association with Dravet syndrome and other SCN1A-related disorders (Dlugos et al., 2007; Harkin et al., 2007; Depienne et al., 2009; Kim et al., 2014; SCN1A Variant Database). This variant alters a highly conserved position predicted to be within the intracellular loop between the S2 and S3 transmembrane segments of the fourth homologous domain of the SCN1A protein, and another missense variant at the same position (R1596L) has also been published in association with SCN1A-related disorders (SCN1A Variant Database). The R1596C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. The R1596C variant is not observed in large population cohorts (Lek et al., 2016). Therefore we consider R1596C to be a pathogenic variant.
Athena Diagnostics Inc RCV000188978 SCV000615039 pathogenic not provided 2016-09-29 criteria provided, single submitter clinical testing
Invitae RCV000794558 SCV000933973 pathogenic Early infantile epileptic encephalopathy with suppression bursts 2018-10-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 1596 of the SCN1A protein (p.Arg1596Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs121917993, ExAC 0.002%). This variant has been observed to be de novo in several individuals with severe epilepsy (PMID:17347258, 26188943, 27781031, 17903680). ClinVar contains an entry for this variant (Variation ID: 68553). 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. This variant disrupts the p.Arg1596 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 21248271, 26188943), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Cavalleri Lab, Royal College of Surgeons in Ireland RCV001031013 SCV001160806 likely pathogenic Generalized epilepsy with febrile seizures plus, type 2 2019-12-11 criteria provided, single submitter research ACMG evidence PS2, PP2, PP3
CeGaT Praxis fuer Humangenetik Tuebingen RCV000188978 SCV001245868 pathogenic not provided 2018-08-01 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV001253159 SCV001428734 pathogenic Severe myoclonic epilepsy in infancy 2020-02-26 criteria provided, single submitter clinical testing This variant was identified as de novo (maternity and paternity confirmed).
UniProtKB/Swiss-Prot RCV000059427 SCV000090951 not provided Focal epilepsy no assertion provided not provided

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