Submissions for variant NM_001165963.4(SCN1A):c.985G>T (p.Gly329Cys)

dbSNP: rs781746113

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000189077	SCV000242708	likely pathogenic	not provided	2015-01-14	criteria provided, single submitter	clinical testing	p.Gly329Cys (GGT>TGT): c.985 G>T in exon 7 of the SCN1A gene (NM_001165963.1) A G329C variant that is likely pathogenic has been identified in the SCN1A gene. The G329C variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G329C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution alters a highly conserved position predicted to be within the extracellular loop between the S5 and S6 transmembrane segments of the first homologous domain of the SCN1A protein (Escayg et al., 2010), and multiple missense mutations in this region of the protein have been reported in association with SCN1A-related disorders in an external mutation database, supporting the functional importance of this region of the protein. Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in INFANTV2-EPIV2-1 panel(s).
Institute of Human Genetics, University of Leipzig Medical Center	RCV001253376	SCV001429055	pathogenic	Severe myoclonic epilepsy in infancy	2018-09-10	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV001255357	SCV001431687	pathogenic	Intellectual disability	2020-08-03	criteria provided, single submitter	clinical testing	The variant c.985G>T, p.(Gly329Cys) was identified in an individual with neurodevelopmental disorder (NDD) and classified as Pathogenic according to ACMG guidelines. Inheritance for this variant was DNV .The variant likely explains the NDD in this individual.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001857651	SCV002125327	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2021-09-21	criteria provided, single submitter	clinical testing	This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with cysteine at codon 329 of the SCN1A protein (p.Gly329Cys). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and cysteine. This missense change has been observed in individual(s) with clinical features of SCN1A-related conditions and/or Dravet syndrome (PMID: 29655203, 32538476). ClinVar contains an entry for this variant (Variation ID: 206933). 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 variant disrupts the p.Gly329 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been observed in individuals with SCN1A-related conditions (PMID: 28084635; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.