Submissions for variant NM_172107.4(KCNQ2):c.1658G>A (p.Arg553Gln)

dbSNP: rs118192234

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000187913	SCV000241515	pathogenic	not provided	2022-02-19	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect with in vitro functional analysis showing that R553Q alters KCNQ2 channel function (Soldovieri et al., 2014; Ambrosino et al., 2015); Not observed in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); This substitution is predicted to be within the C-terminal cytoplasmic domain; 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: 11690625, 26073431, 16686649, 18698150, 19380078, 12754513, 28976808, 31780880, 27535030, 20437616, 32718099, 27602407, 24375629)
CeGaT Center for Human Genetics Tuebingen	RCV000187913	SCV001247374	pathogenic	not provided	2024-08-01	criteria provided, single submitter	clinical testing	KCNQ2: PS2, PM1, PM2, PM5, PS4:Moderate, PP3, PS3:Supporting
Labcorp Genetics (formerly Invitae), Labcorp	RCV001248564	SCV001422062	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2024-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 553 of the KCNQ2 protein (p.Arg553Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with KCNQ2-related disease (PMID: 24375629, 29933521). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 21767). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt KCNQ2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KCNQ2 function (PMID: 24375629, 26073431). This variant disrupts the p.Arg553 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23621294, 27535030). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000187913	SCV005198555	pathogenic	not provided	2022-10-18	criteria provided, single submitter	clinical testing
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV004798741	SCV005420641	pathogenic	Developmental and epileptic encephalopathy, 7	2024-10-04	criteria provided, single submitter	research	PS2,PS3,PM5,PM2,PP3
GeneReviews	RCV000678060	SCV000041618	not provided	Seizures, benign familial neonatal, 1		no assertion provided	literature only	BFNE (benign familial neonatal epilepsy)