Submissions for variant NM_001165963.4(SCN1A):c.2994C>A (p.Asp998Glu)

dbSNP: rs796052991

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188907	SCV000242537	uncertain significance	not provided	2021-06-04	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27535533, 29655203, 26582918, 24077912)
Lifecell International Pvt. Ltd	RCV001509553	SCV001712080	likely pathogenic	Severe myoclonic epilepsy in infancy		criteria provided, single submitter	clinical testing	A heterozygous missense variant (c.2994C>A) in exon 19 of the SCN1A gene that results in the amino acid substitution from Aspartic acid to Glutamic acid at codon 998 (p.Asp998Glu) was identified. The observed variant is not present in both the 1000 Genomes and gnomAD databases. The reference base is conserved across the species and in-silico predictions by Polyphen and SIFT are damaging. A different amino acid substitution at the same position (Asp998Gly) has been reported in a patient with Dravet syndrome (Depienne et al., 2009). The Missense Variants Z-Score for this variant is 5.61. Missense Variants Z-Score is produced by the Exome Aggregation Consortium (60,706 adult humans) by computing a signed Z score for the deviation of observed counts from the expected number. Positive Z scores indicate increased constraint (intolerance to variation) and therefore that the gene had fewer missense variants than expected. (DOI: 10.1038/nature19057). The MPC score for this variant is 2.02. MPC score is computed on an analysis of the ExAC population frequencies, the Missense Badness Score is the normalized fold difference of observed versus expected missense substitutions in sub-genic regions. This score is then combined with orthogonal deleteriousness metrics into one score called MPC (for Missense badness, PolyPhen-2, and Constraint) designed to classify whether a missense variant is deleterious. (DOI: 10.1101/148353). Based on the above evidence this variant has been classified as likely pathogenic according to the ACMG guidelines
Invitae	RCV002514043	SCV003020165	likely pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2023-12-04	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 998 of the SCN1A protein (p.Asp998Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of autosomal dominant SCN1A-related conditions and/or SCN1A-related conditions (PMID: 29655203; Invitae). ClinVar contains an entry for this variant (Variation ID: 206795). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SCN1A protein function with a positive predictive value of 95%. This variant disrupts the p.Asp998 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been observed in individuals with SCN1A-related conditions (PMID: 18930999), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV003448283	SCV004176673	uncertain significance	Developmental and epileptic encephalopathy 6B	2023-02-14	criteria provided, single submitter	clinical testing