Submissions for variant NM_001165963.4(SCN1A):c.3714A>C (p.Glu1238Asp)

gnomAD frequency: 0.00008  dbSNP: rs121917973

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723903	SCV000203502	uncertain significance	not provided	2014-04-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000723903	SCV000242554	uncertain significance	not provided	2023-10-24	criteria provided, single submitter	clinical testing	Reported multiple times in patients with epilepsy in published literature; however, parental testing was not reported, and one individual was also found to have a second SCN1A variant (Harkin et al., 2007; Zuberi et al., 2011; Kodera et al., 2013; SCN1A Variant Database); This substitution is predicted to be within the extracellular loop between the S1 and S2 transmembrane segments of the third homologous domain; Observed in heterozygous state in many unrelated healthy adult individuals tested at GeneDx; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; This variant is associated with the following publications: (PMID: 16713913, 17166794, 23884151, 19586930, 21248271, 28150151, 16713920, 23662938, 19585586, 24136861, 18804930, 32090326, 32180723, 31054490, 17347258, 35074891)
Mendelics	RCV000059405	SCV001136036	uncertain significance	Severe myoclonic epilepsy in infancy	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000723903	SCV001247843	uncertain significance	not provided	2020-01-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001476333	SCV001680541	likely benign	Early infantile epileptic encephalopathy with suppression bursts	2023-12-22	criteria provided, single submitter	clinical testing
New York Genome Center	RCV001836728	SCV002097709	uncertain significance	Severe myoclonic epilepsy in infancy; Generalized epilepsy with febrile seizures plus, type 2	2021-09-17	criteria provided, single submitter	clinical testing	The inherited c.3714A>C (p.Glu1238Asp) variant identified in the SCN1A gene substitutes a very well conserved Glutamic Acid for AsparticAcid at amino acid 1238/1999 (exon 22/29). SCN1A is an alternatively spliced transcript and this variant is also called c.3681A>C (p.Glu1227Asp) when annotated from transcript NM_006920.6. This variant is found with low frequency in gnomAD(v3.1.1) (13 heterozygotes, 0 homozygotes; allele frequency:8.6e-5) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Damaging (SIFT; score:0.00) and Pathogenic (REVEL; score:0.9269) to the function of the canonical transcript. This variant is reported as a Variant of Uncertain Significance in ClinVar (VarID:68532), and has beenidentified in several affected individuals in the literature, [PMID:31054490; PMID:23662938; PMID:17347258]. The p.Glu1238 reside is within the extracellular loop between the S1and S2 domains of the 3rd homologous domain. The inherited c.3714A>C (p.Glu1238Asp) variant identified in the SCN1A gene is reported as a Variant of Uncertian Significance.
UniProtKB/Swiss-Prot	RCV000059405	SCV000090929	not provided	Severe myoclonic epilepsy in infancy		no assertion provided	not provided