Submissions for variant NM_001165963.4(SCN1A):c.3899C>T (p.Thr1300Ile)

gnomAD frequency: 0.00019  dbSNP: rs146878122

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000724898	SCV000242564	likely benign	not provided	2020-12-02	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 29948376)
Eurofins Ntd Llc (ga)	RCV000724898	SCV000332268	uncertain significance	not provided	2015-06-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000471568	SCV000548773	likely benign	Early infantile epileptic encephalopathy with suppression bursts	2025-01-22	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000188933	SCV000596951	uncertain significance	not specified	2017-05-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002314753	SCV000848167	likely benign	Inborn genetic diseases	2021-09-15	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Mendelics	RCV000986884	SCV001136033	likely benign	Severe myoclonic epilepsy in infancy	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000188933	SCV003800870	likely benign	not specified	2023-01-11	criteria provided, single submitter	clinical testing	Variant summary: SCN1A c.3899C>T (p.Thr1300Ile) 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 0.00016 in 250156 control chromosomes (gnomAD). The observed variant frequency is approximately 9 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.3899C>T has been reported in the literature in the heterozygous state in twin siblings affected with juvenile myoclonic epilepsy, however both parents also carried the variant and were unaffected (Landoulsi_2018). The siblings and mother from this family were also heterozygous for a variant in MAST4 (c.4486G>A, p.Val1496Met), but without strong evidence for pathogenicity. Thus this report does not provide unequivocal conclusions about association of c.3899C>T with SCN1A-Related Seizure Disorder. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified it as either likely benign (n=4) or VUS (n=3). Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV000724898	SCV004033775	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	SCN1A: PP2, BS2
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV001252612	SCV001428371	uncertain significance	Intellectual disability	2019-01-01	no assertion criteria provided	clinical testing