Submissions for variant NM_001165963.4(SCN1A):c.3749C>T (p.Thr1250Met)

gnomAD frequency: 0.00025  dbSNP: rs140731963

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188927	SCV000242557	benign	not provided	2019-02-27	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27231140, 19522081, 21719429, 28202706, 28150151, 26990884, 31009440)
Mendelics	RCV000986886	SCV001136035	benign	Severe myoclonic epilepsy in infancy	2023-08-22	criteria provided, single submitter	clinical testing
Invitae	RCV001413415	SCV001615528	likely benign	Early infantile epileptic encephalopathy with suppression bursts	2021-11-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002517010	SCV003719702	benign	Inborn genetic diseases	2022-06-17	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235112	SCV003934754	benign	not specified	2023-05-10	criteria provided, single submitter	clinical testing	Variant summary: SCN1A c.3749C>T (p.Thr1250Met) results in a non-conservative amino acid change located in the ion transport domain (IPR005821) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00041 in 249310 control chromosomes. The observed variant frequency is approximately 23-fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN1A causing SCN1A-Related Seizure Disorder phenotype (1.8e-05), strongly suggesting that the variant is benign. c.3749C>T has been reported in the literature in individuals affected with Seizure Disorders, without evidence for causality (i.e. lack of segregation or segregation data not provided) and in one case where the variant co-occurred with a pathogenic variant (c.3706-2A>G), providing supporting evidence for a benign role (e.g. Orrico_2009, Catarino_2011, Lal_2016, Fang_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21719429, 19522081, 31009440, 26990884). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either benign (n=2)/likely benign (n=1), or VUS (=1). Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV000188927	SCV004011233	likely benign	not provided	2023-04-01	criteria provided, single submitter	clinical testing	SCN1A: PP2, BS1
PreventionGenetics, part of Exact Sciences	RCV003947582	SCV004764092	likely benign	SCN1A-related condition	2021-02-10	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).