Submissions for variant NM_004519.4(KCNQ3):c.1091G>A (p.Arg364His)

gnomAD frequency: 0.00001  dbSNP: rs1204519015

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001203500	SCV001374668	pathogenic	Benign neonatal seizures	2024-04-05	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 364 of the KCNQ3 protein (p.Arg364His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with benign familial infantile epilepsy (BFIE) (PMID: 25278462). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 934997). 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 KCNQ3 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg364 amino acid residue in KCNQ3. 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. For these reasons, this variant has been classified as Pathogenic.
New York Genome Center	RCV001291726	SCV001480312	likely pathogenic	Seizures, benign familial neonatal, 2	2019-10-11	criteria provided, single submitter	clinical testing	The inherited heterozygous p.Arg364His missense variant identified in the KCNQ3 gene is reported once in the gnomAD database (1 out of 282,434 heterozygous alleles) indicating it’s a rare allele in the populations represented in gnomAD. The variant affects a highly conserved residue and is predicted deleterious by multiple in silico prediction tools. Most of the disease-causing variants in KCNQ3 reported to-date are missense The proband has inherited this variant from similarly affected parent. In the literature, the p.Arg364His variant has been reported as de novo in a child with infantile convulsions and partial epilepsy with centrotemporal spikes [PMID: 25278462]. The patient had normal cerebral MRI and EEG, normal psychomotor development, and had a cluster of seizures characterized by hemifacial motor seizures, clonic contractions of limbs with hypertonia, with a tendency to evolve into generalized tonic clonic seizures [PMID: 25278462]. Based on the available evidence, the p.Arg364His variant is assessed here as likely pathogenic.
GeneDx	RCV001565213	SCV001788519	pathogenic	not provided	2024-06-10	criteria provided, single submitter	clinical testing	De novo variant with confirmed parentage in a patient with epilepsy previously tested at GeneDx and identified as apparently de novo in a patient with infantile onset epilepsy in published literature (PMID: 25278462); Not observed at significant frequency in large population cohorts (gnomAD); 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: 25278462, 35384780)
GeneReviews	RCV001291726	SCV002061341	not provided	Seizures, benign familial neonatal, 2		no assertion provided	literature only	Late-infantile staring spells at age 2 yrs, generalized convulsive seizures and CTS on EEG