Submissions for variant NM_001165963.4(SCN1A):c.5951C>A (p.Pro1984His)

gnomAD frequency: 0.00074  dbSNP: rs146733308

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723619	SCV000111475	uncertain significance	not provided	2013-04-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000723619	SCV000242659	benign	not provided	2021-03-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002313760	SCV000847661	benign	Inborn genetic diseases	2019-03-07	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Fulgent Genetics, Fulgent Genetics	RCV000764282	SCV000895301	uncertain significance	Migraine, familial hemiplegic, 3; Severe myoclonic epilepsy in infancy; Generalized epilepsy with febrile seizures plus, type 2	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV001080157	SCV001008820	likely benign	Early infantile epileptic encephalopathy with suppression bursts	2024-01-15	criteria provided, single submitter	clinical testing
New York Genome Center	RCV001281471	SCV001468779	uncertain significance	Seizure	2019-06-02	criteria provided, single submitter	clinical testing	The SCN1A c.5951C>A (p.Pro1984His) variant identified substitutes a highly conserved Proline for Histidine at amino acid 1973/1999 (coding exon 29/29). In silico algorithms predict this variant to be Deleterious (Provean; score:-6.60) and Damaging (SIFT; score:0.00) to the function of the canonical transcript. The c.5951C>A (p.Pro1984His) variant has been reported in ClinVar as a Variant of Uncertain Significance (VarID: 93661), and has been reported a single time in a large cohort study of pediatric patients with drug resistant epilepsy [PMID: 29353705], with no patient specific phenotype information. Given the lack of compelling information supporting its pathogenicity, the c.5951C>A (p.Pro1984His) variant identified in the SCN1A gene is reported here as a Variant of Uncertain Significance.
PreventionGenetics, part of Exact Sciences	RCV004542757	SCV004770749	likely benign	SCN1A-related disorder	2023-05-23	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000723619	SCV001549488	likely benign	not provided		no assertion criteria provided	clinical testing	The SCN1A p.P1984H variant was not identified in the literature but was identified in dbSNP (ID: rs146733308) and ClinVar (classified as uncertain significance by GeneDx, EGL Genetic Diagnostics, and Fulgent Genetics; as likely benign by Invitae; and as benign by Ambry Genetics). The variant was identified in control databases in 61 of 282118 chromosomes at a frequency of 0.0002162, and was observed at the highest frequency in the African population in 59 of 24952 chromosomes (freq: 0.002365) (Genome Aggregation Database March 6, 2019, v2.1.1). This frequency is greater than expected for the rare, autosomal dominant epilepsy with febrile seizures and early infantile epileptic encephalopathy conditions associated with SCN1A variants. The p.P1984 residue is conserved in mammals and more distantly related organisms, and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.