Submissions for variant NM_001165963.4(SCN1A):c.4094G>A (p.Gly1365Asp)

dbSNP: rs1691073965

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001089990	SCV001244982	pathogenic	Severe myoclonic epilepsy in infancy	2018-06-21	criteria provided, single submitter	clinical testing	A heterozygous missense variant, NM_001165963.1(SCN1A):c.4094G>A, has been identified in exon 21 of 26 of the SCN1A gene. The variant is predicted to result in a moderate amino acid change from glycine to aspartic acid at position 1365 of the protein (NP_001159435.1(SCN1A):p.(Gly1365Asp)). The glycine residue at this position has very high conservation (100 vertebrates, UCSC), and is located within the ion transport domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is absent in population databases (gnomAD, dbSNP, 1000G), and has previously been reported as a de novo mutation in association with severe myoclonic epilepsy in infancy (SMEI), however, no additional information was provided (SCN1A variant database). A different variant in the same codon resulting in a change to serine has also been reported to cause SMEI (SCN1A variant database). Analysis of parental samples indicated this variant is de novo. Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001862667	SCV002303584	likely pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2023-07-03	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 870417). 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. This variant disrupts the p.Gly1365 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been observed in individuals with SCN1A-related conditions (PMID: 31001185), which suggests that this may be a clinically significant amino acid residue. 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. This missense change has been observed in individual(s) with developmental and epileptic encephalopathy (PMID: 32573669; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1365 of the SCN1A protein (p.Gly1365Asp).