Submissions for variant NM_172107.4(KCNQ2):c.1678C>T (p.Arg560Trp)

dbSNP: rs773171451

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000187915	SCV000241517	pathogenic	not provided	2022-04-02	criteria provided, single submitter	clinical testing	Functional studies show that R560W (reported as R532W using alternative nomenclature) alters the expression and function of the Kv7.2 and Kv7.3 potassium channels (Orhan et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 31152295, 24318194, 22275249, 27652284, 28488083, 25880994, 31832524, 32139178, 32573669, 32581362, 33192566, 30008368, 32917465, 33726816, 31175295, 27602407)
Invitae	RCV000462637	SCV000543193	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2023-05-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 560 of the KCNQ2 protein (p.Arg560Trp). 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: 22275249, 25880994). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 205915). 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. Experimental studies have shown that this missense change affects KCNQ2 function (PMID: 24318194). For these reasons, this variant has been classified as Pathogenic.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000678188	SCV000930223	likely pathogenic	Developmental and epileptic encephalopathy, 7	2019-04-27	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000678188	SCV001245036	pathogenic	Developmental and epileptic encephalopathy, 7	2020-11-05	criteria provided, single submitter	clinical testing	0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with early infantile epileptic encephalopathy, 7 (EIEE) (MIM#613720) and benign neonatal seizures, 1 (BNS) (MIM# 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance, however, this is only reported for patients with BNS (PMID 25959266). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated KCNQ voltage-gated potassium channel (NCBI, PDB). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. An alternative change (p.Arg560Gln) has been reported as likely pathogenic (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic, and has been observed in several de novo patients with EIEE (Decipher, ClinVar, PMID: 22275249, PMID: 25880994). (SP) 1207 - Parental origin of the variant is unresolved. This variant was not maternally inherited (20G001811). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Institute of Human Genetics, University of Leipzig Medical Center	RCV000678188	SCV001428916	pathogenic	Developmental and epileptic encephalopathy, 7	2021-10-26	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PS2, PS3_MOD, PS4_MOD, PM1, PM5, PM2_SUP, PP3
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	RCV001374917	SCV001572204	pathogenic	Neurodevelopmental disorder	2021-02-24	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000187915	SCV002023228	pathogenic	not provided	2019-06-26	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000678188	SCV002581023	pathogenic	Developmental and epileptic encephalopathy, 7	2022-06-24	criteria provided, single submitter	clinical testing
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000187915	SCV002818234	pathogenic	not provided	2022-12-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002514018	SCV003661479	pathogenic	Inborn genetic diseases	2022-01-14	criteria provided, single submitter	clinical testing	The c.1678C>T (p.R560W) alteration is located in exon 15 (coding exon 15) of the KCNQ2 gene. This alteration results from a C to T substitution at nucleotide position 1678, causing the arginine (R) at amino acid position 560 to be replaced by a tryptophan (W). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been detected in multiple individuals with neonatal epileptic encephalopathy (Kim, 2021; Na, 2020, Ma, 2019, Australian Genomics Health Alliance Acute Care Flagship, 2020) and has been found to be de novo in several unrelated affected individuals (Xu, 2021; Weckhuysen, 2012; Pisano, 2015; Oates, 2018; Fang, 2019). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000678188	SCV004100583	pathogenic	Developmental and epileptic encephalopathy, 7		criteria provided, single submitter	clinical testing
GeneReviews	RCV000678188	SCV000484637	not provided	Developmental and epileptic encephalopathy, 7		no assertion provided	literature only	EE (epileptic encephalopathy)
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001003634	SCV001162061	likely pathogenic	Global developmental delay; Absent speech; Limb dystonia		no assertion criteria provided	research
Channelopathy-Associated Epilepsy Research Center	RCV003315322	SCV004015104	not provided	Complex neurodevelopmental disorder		no assertion provided	literature only