Submissions for variant NM_172107.4(KCNQ2):c.1687G>A (p.Asp563Asn)

dbSNP: rs796052653

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000187917	SCV000241519	pathogenic	not provided	2020-09-15	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a decrease in PIP2 apparent affinity and a reduction in channel function; reported using alternate nomenclature D535N (Ambrosino et al., 2018); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This substitution is predicted to be within the C-terminal cytoplasmic domain; This variant is associated with the following publications: (PMID: 24107868, 23621294, 31172278, 25959266, 26007637, 27334371, 29383681, 32581083, 30669290, 32651551)
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000187917	SCV000510747	pathogenic	not provided	2016-12-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002317111	SCV000851385	pathogenic	Inborn genetic diseases	2016-06-09	criteria provided, single submitter	clinical testing	The p.D563N pathogenic mutation (also known as c.1687G>A), located in coding exon 15 of the KCNQ2 gene, results from a G to A substitution at nucleotide position 1687. The aspartic acid at codon 563 is replaced by asparagine, an amino acid with highly similar properties. This mutation has been detected as a de novo occurrence with confirmed paternity in three unrelated individuals with neonatal epileptic encephalopathy diagnoses before age one month (Weckhuysen S, et al. Neurology 2013;81(19):1697-703; Milh M, et al. Am. J. Med. Genet. A 2015; 167A(10):2314-8). In addition, a different alteration located at the same position, p.D563E, was detected as a de novo occurrence with confirmed paternity in an individual with early onset epileptic encephalopathy (Kato M, et al. Epilepsia 2013 Jul; 54(7):1282-7). Based on the supporting evidence, p.D563N is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics	RCV000763450	SCV000894226	pathogenic	Seizures, benign familial neonatal, 1; Developmental and epileptic encephalopathy, 7	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000810995	SCV000951238	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2023-03-23	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp563 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23621294, 27334371). 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: 29383681). 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. ClinVar contains an entry for this variant (Variation ID: 205917). This variant is also known as D535N. This missense change has been observed in individual(s) with benign familial neonatal seizures (PMID: 24107868, 26007637). 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 aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 563 of the KCNQ2 protein (p.Asp563Asn).
CeGaT Center for Human Genetics Tuebingen	RCV000187917	SCV001247373	pathogenic	not provided	2020-03-01	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000187917	SCV002502882	pathogenic	not provided	2020-05-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000187917	SCV003818799	pathogenic	not provided	2022-02-22	criteria provided, single submitter	clinical testing
GeneReviews	RCV000678190	SCV000484639	not provided	Developmental and epileptic encephalopathy, 7		no assertion provided	literature only	EE (epileptic encephalopathy)
Center of Excellence for Medical Genomics, Chulalongkorn University	RCV000678190	SCV002564405	pathogenic	Developmental and epileptic encephalopathy, 7	2022-08-19	no assertion criteria provided	research
Center of Excellence for Medical Genomics, Chulalongkorn University	RCV002281569	SCV002570028	pathogenic	Seizures, benign familial neonatal, 1	2002-09-08	no assertion criteria provided	research