Submissions for variant NM_172107.4(KCNQ2):c.937G>T (p.Gly313Trp)

dbSNP: rs796052639

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000187887	SCV000241489	uncertain significance	not provided	2013-11-04	criteria provided, single submitter	clinical testing	p.Gly313Trp (GGG>TGG): c.937 G>T in exon 7 of the KCNQ2 gene (NM_172107.2)The Gly313Trp missense change 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. This variant is a conservative amino acid substitution, as Glycine and Tryptophan are both uncharged, non-polar amino acids. It alters a highly conserved position in the cytoplasmic domain of the protein, and other missense substitutions have been reported in this region of the protein in association with epilepsy. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether Gly313Trp is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Invitae	RCV003753099	SCV004407721	likely pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2023-02-24	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 313 of the KCNQ2 protein (p.Gly313Trp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with KCNQ2-related conditions. ClinVar contains an entry for this variant (Variation ID: 205890). 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 KCNQ2 protein function. This variant disrupts the p.Gly313 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.