Submissions for variant NM_172107.4(KCNQ2):c.1741C>G (p.Arg581Gly)

dbSNP: rs118192236

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255557	SCV000322210	pathogenic	not provided	2016-06-27	criteria provided, single submitter	clinical testing	The R581G variant has been previously reported as a de novo pathogenic variant, identified by whole exome sequencing, in an individual with epileptic encephalopathy (EuroEpinomics-RES Consortium, 2014). 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. The R581G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution alters a conserved position predicted to be within the C-terminal cytoplasmic domain. In silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, missense variants in a nearby residue (M578V/I) have been reported in the Human Gene Mutation Database in association with KCNQ2-related disorders (Stenson et al., 2014).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001222134	SCV001394218	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2024-05-06	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 581 of the KCNQ2 protein (p.Arg581Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early infantile epileptic encephalopathy (PMID: 25262651, 30174244). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 265380). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Arg581 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27864847, 28133863, 28973083). 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.
GeneReviews	RCV000678196	SCV000484645	not provided	Developmental and epileptic encephalopathy, 7		no assertion provided	literature only	EE (epileptic encephalopathy)