ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.4787G>A (p.Arg1596His) (rs575368466)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000518137 SCV000615040 pathogenic not provided 2017-05-09 criteria provided, single submitter clinical testing
GeneDx RCV000518137 SCV000617205 uncertain significance not provided 2020-01-09 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21248271, 28150151, 26188943, 31009440, 32090326)
Invitae RCV000690853 SCV000818582 pathogenic Early infantile epileptic encephalopathy with suppression bursts 2020-10-14 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1596 of the SCN1A protein (p.Arg1596His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs575368466, ExAC 0.01%). This variant has been observed to segregate with early onset epileptic encephalopathy and/or febrile seizures in several families (PMID: 26188943, 21248271). ClinVar contains an entry for this variant (Variation ID: 448255). 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 identified in the SCN1A gene is located in the cytoplasmic D4-S2/S3 region of the resulting protein (PMID: 25348405, 18804930). Variants that disrupt the p.Arg1596 amino acid residue in SCN1A have been observed in affected individuals (PMID: 18930999, 24328833, 28202706). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000518137 SCV001152503 likely pathogenic not provided 2019-05-01 criteria provided, single submitter clinical testing

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