ClinVar Miner

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

dbSNP: rs773171451
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Total submissions: 14
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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 Centre For Genomic Medicine, NCGM 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

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