Submissions for variant NM_001165963.4(SCN1A):c.2659G>A (p.Val887Met)

gnomAD frequency: 0.00001  dbSNP: rs368663649

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000307557	SCV000334134	uncertain significance	not provided	2015-08-13	criteria provided, single submitter	clinical testing
GeneDx	RCV000307557	SCV002569707	uncertain significance	not provided	2022-03-04	criteria provided, single submitter	clinical testing	Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This substitution is predicted to be within the intracellular loop between the S4 and S5 transmembrane segments of the second homologous domain; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV002521885	SCV003469464	uncertain significance	Early infantile epileptic encephalopathy with suppression bursts	2024-08-23	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 887 of the SCN1A protein (p.Val887Met). This variant is present in population databases (rs368663649, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of familial hemiplegic migraine and/or recurrent seizures (internal data). ClinVar contains an entry for this variant (Variation ID: 282593). 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.
Ambry Genetics	RCV003362741	SCV004078776	likely benign	Inborn genetic diseases	2023-07-10	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004782337	SCV005394911	uncertain significance	not specified	2024-09-11	criteria provided, single submitter	clinical testing	Variant summary: SCN1A c.2659G>A (p.Val887Met) results in a conservative amino acid change located in the Ion transport domain 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 2.4e-05 in 251362 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.2659G>A 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: 282593). Based on the evidence outlined above, the variant was classified as uncertain significance.