Submissions for variant NM_172107.4(KCNQ2):c.998G>A (p.Arg333Gln)

dbSNP: rs118192216

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413623	SCV000491166	pathogenic	not provided	2024-11-11	criteria provided, single submitter	clinical testing	Reported in association with benign familial neonatal seizures (BFNS) (PMID: 14534157); Published functional studies demonstrate that R333Q moderately reduces channel function (PMID: 14534157, 30126342); 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: 19380078, 31832524, 18698150, 16686649, 29215089, 33897753, 31152295, 30126342, 30669290, 33754465, 31440721, 14534157, 27602407, 37596007)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000813877	SCV000954258	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2024-09-10	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 333 of the KCNQ2 protein (p.Arg333Gln). This variant is present in population databases (rs118192216, gnomAD 0.0009%). This missense change has been observed in individuals with infantile seizures (PMID: 14534157, 29215089; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 21810). 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: 14534157, 30126342). This variant disrupts the p.Arg333 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16039833, 23621294, 23692823). 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.
Revvity Omics, Revvity	RCV000413623	SCV003818788	pathogenic	not provided	2022-11-10	criteria provided, single submitter	clinical testing
GeneReviews	RCV000678102	SCV000041668	not provided	Seizures, benign familial neonatal, 1		no assertion provided	literature only	BFNE (benign familial neonatal epilepsy)
Channelopathy-Associated Epilepsy Research Center	RCV003315306	SCV004015107	not provided	Complex neurodevelopmental disorder		no assertion provided	literature only