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

dbSNP: rs575368466

Total submissions: 6

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	2022-06-10	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (gnomAD); This substitution is predicted to be in the intracellular loop between the S2 and S3 transmembrane segments of the fourth homologous domain; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 21248271, 28150151, 31009440, 34055682, 35571373, 32090326, 26188943)
Invitae	RCV000690853	SCV000818582	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1596 of the SCN1A protein (p.Arg1596His). This variant is present in population databases (rs575368466, gnomAD 0.007%). This missense change has been observed in individual(s) with early onset epileptic encephalopathy and/or febrile seizures (PMID: 21248271, 26188943). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 448255). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SCN1A protein function with a positive predictive value of 95%. This variant disrupts the p.Arg1596 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18804930, 18930999, 24328833, 25348405, 28202706). 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 Center for Human Genetics Tuebingen	RCV000518137	SCV001152503	pathogenic	not provided	2022-01-01	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002289705	SCV002581467	likely pathogenic	Severe myoclonic epilepsy in infancy	2022-04-05	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000518137	SCV003810086	likely pathogenic	not provided	2022-02-04	criteria provided, single submitter	clinical testing