ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.2791C>T (p.Arg931Cys) (rs121918788)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000188897 SCV000203506 likely pathogenic not provided 2014-04-30 criteria provided, single submitter clinical testing
GeneDx RCV000188897 SCV000242527 pathogenic not provided 2017-02-01 criteria provided, single submitter clinical testing The Arg931Cys missense variant in the SCN1A gene has been reported as a de novo variant in multiple patients with Dravet syndrome and other SCN1A-related disorders (Ohmori et al., 2002; Depienne et al., 2009; an external mutation database). This amino acid substitution is non-conservative, as a positively charged Arginine residue is replaced by an uncharged Cysteine residue, and the gain of a Cysteine could affect disulfide bond formation in the protein. Arg931Cys alters a highly conserved position in the pore loop between the S5 and S6 segments of the second transmembrane domain, and many other variants have been reported in this region of the protein.
Invitae RCV000636409 SCV000757848 pathogenic Early infantile epileptic encephalopathy with suppression bursts 2020-06-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 931 of the SCN1A protein (p.Arg931Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in individuals affected with Dravet syndrome (PMID: 12083760, 18076640). This variant is also known as Arg921Cys in the literature. ClinVar contains an entry for this variant (Variation ID: 68598). 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.Arg931 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25243660, 27231140, 28079314). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000188897 SCV001248481 pathogenic not provided 2018-07-01 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000059475 SCV001426157 pathogenic Severe myoclonic epilepsy in infancy 2018-07-25 criteria provided, single submitter clinical testing
UniProtKB/Swiss-Prot RCV000059475 SCV000091000 not provided Severe myoclonic epilepsy in infancy no assertion provided not provided

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