Submissions for variant NM_172107.4(KCNQ2):c.740C>G (p.Ser247Trp)

dbSNP: rs74315392

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001059860	SCV001224511	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2022-07-11	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with clinical features of KCNQ2-related conditions (PMID: 12742592; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 247 of the KCNQ2 protein (p.Ser247Trp). ClinVar contains an entry for this variant (Variation ID: 7389). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser247 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29314763, 31199083). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects KCNQ2 function (PMID: 12742592). 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.
GeneDx	RCV003441710	SCV004170645	pathogenic	not provided	2023-10-07	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect showing a reduction of the channel current (Dedek et al., 2003); Not observed at significant frequency in large population cohorts (gnomAD); The majority of missense variants in this gene are considered pathogenic (HGMD); This substitution is predicted to be within the transmembrane segment S5; This variant is associated with the following publications: (PMID: 19818940, 17129708, 19380078, 32770121, 12742592)
OMIM	RCV000030664	SCV000028017	pathogenic	Developmental and epileptic encephalopathy, 7	2003-04-01	no assertion criteria provided	literature only
GeneReviews	RCV000678092	SCV000041655	not provided	Seizures, benign familial neonatal, 2		no assertion provided	literature only	.Identified in a boy with EE (EE (epileptic encephalopathy); mother with BNE (benign neonatal epilepsy) (possible mosaicism; uncertain severity)