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 2017-08-25 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SCN1A gene. The R1596H variant has been reported to segregate with seizures in multiple affected individuals from several families with generalized epilepsy with febrile seizures plus (GEFS+) and other SCN1A-related disorders; however, R1596H was also identified in asymptomatic family members, possibly indicating incomplete penetrance (Hoffman-Zacharska et al., 2015; Zuberi et al., 2011). The R1596H variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is predicted to be within the intracellular loop between the S2 and S3 transmembrane segments of the fourth homologous domain. Other missense variants at the same position (R1596C and R1596L) have been reported as de novo variants in association with Dravet syndrome and other SCN1A-related disorders, supporting the functional importance of this position in the protein; however, the R1596H is a more conservative amino acid substitution (Dlugos et al., 2007; Harkin et al., 2007; Depienne et al., 2009). In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000690853 SCV000818582 pathogenic Early infantile epileptic encephalopathy 2019-11-16 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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