ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.3734G>A (p.Arg1245Gln) (rs121917912)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188926 SCV000242556 pathogenic not provided 2014-04-30 criteria provided, single submitter clinical testing p.Arg1245Gln (CGA>CAA): c.3734 G>A in exon 19 of the SCN1A gene (NM_001165963.1) The R1245Q mutation in SCN1A has been reported previously as a de novo mutation in a proband with severe myoclonic epilepsy of infancy (Mancardi et al, 2006). R1245Q is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs in the extracellular loop between transmembrane segments S1 and S2 in the third homologous domain at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. The variant is found in EPILEPSY panel(s).
Invitae RCV000636387 SCV000757826 likely pathogenic Early infantile epileptic encephalopathy with suppression bursts 2018-08-15 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1245 of the SCN1A protein (p.Arg1245Gln). 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 individuals affected with severe myoclonic epilepsy of infancy, in one of whom it was found de novo (PMID: 17054684, 21906962, 28202706). ClinVar contains an entry for this variant (Variation ID: 68533). This variant identified in the SCN1A gene is located in the extracellular D3-S1/S2 region of the resulting protein (PMID: 25348405, 18804930), but it is unclear how this variant impacts the function of this protein. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C35"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
UniProtKB/Swiss-Prot RCV000059406 SCV000090930 not provided Severe myoclonic epilepsy in infancy no assertion provided not provided

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