Submissions for variant NM_001165963.4(SCN1A):c.2057A>C (p.Glu686Ala)

gnomAD frequency: 0.00005  dbSNP: rs374767754

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000430819	SCV000334749	uncertain significance	not provided	2015-09-01	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000430819	SCV000511240	uncertain significance	not provided	2016-09-28	criteria provided, single submitter	clinical testing	Converted during submission to Uncertain significance.
GeneDx	RCV000430819	SCV000565527	likely benign	not provided	2020-04-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001043886	SCV001207655	uncertain significance	Early infantile epileptic encephalopathy with suppression bursts	2024-10-30	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 686 of the SCN1A protein (p.Glu686Ala). This variant is present in population databases (rs374767754, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with SCN1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 282982). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SCN1A protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Revvity Omics, Revvity	RCV000430819	SCV003820736	uncertain significance	not provided	2021-04-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005055820	SCV005727236	uncertain significance	not specified	2024-11-04	criteria provided, single submitter	clinical testing	Variant summary: SCN1A c.2057A>C (p.Glu686Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251138 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2057A>C in individuals affected with SCN1A-Related Seizure Disorder and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 282982). Based on the evidence outlined above, the variant was classified as uncertain significance.