ClinVar Miner

Submissions for variant NM_172107.4(KCNQ2):c.1678C>T (p.Arg560Trp) (rs773171451)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000187915 SCV000241517 pathogenic not provided 2018-06-12 criteria provided, single submitter clinical testing p.Arg560Trp (CGG>TGG): c.1678 C>T in exon 15 of the KCNQ2 gene (NM_172107.2) The R560W mutation in the KCNQ2 gene has been previously reported as a mutation in an individual with an onset of tonic seizures and myoclonic jerks at day 3 of life (Weckhuysen, et al., 2012). Functional studies show that the R560W mutation (reported as R532W using alternative nomenclature) alters the expression and function of the Kv7.2 and Kv7.3 potassium channels (Orhan et al., 2014). It 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. R560W alters a highly conserved position in the carboxy terminus of the KCNQ2 protein and other missense mutations have been reported in this region of the protein in association with epilepsy. Therefore, R560W is considered a disease-causing mutation, and its presence is consistent with a diagnosis of a KCNQ2-related disorder. The variant is found in EPILEPSY,INFANT-EPI panel(s).
Invitae RCV000462637 SCV000543193 pathogenic Early infantile epileptic encephalopathy 2019-06-04 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 560 of the KCNQ2 protein (p.Arg560Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in 2 individuals affected with early-infantile epileptic encephalopathy (PMID: 22275249, 25880994). ClinVar contains an entry for this variant (Variation ID: 205915). An experimental study has shown that this missense change (called R532W) disrupts KCNQ2 channel function, likely due to decreased cell-surface expression of the protein (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 Early infantile epileptic encephalopathy 7 2019-04-27 criteria provided, single submitter clinical testing
Victorian Clinical Genetics Services,Murdoch Childrens Research Institute RCV000678188 SCV001245036 pathogenic Early infantile epileptic encephalopathy 7 2018-12-17 criteria provided, single submitter clinical testing A heterozygous missense variant, NM_172107.3(KCNQ2):c.1678C>T, has been identified in exon 15 of 17 of the KCNQ2 gene. The variant is predicted to result in a major amino acid change from arginine to tryptophan at position 560 of the protein, NP_742105.1(KCNQ2):p.(Arg560Trp). The arginine residue at this position has very high conservation (100 vertebrates, UCSC), and is located within the KCNQ channel functional domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is absent in population databases (gnomAD, dbSNP, 1000G). This variant has previously been reported as pathogenic in patients with early infantile epileptic encephalopathy (ClinVar). It has also been shown to be de novo in two further cases (Weckhuysen, S., et al. (2012), Pisano, T., et al. (2015)). In addition, functional analysis of cells expressing the variant demonstrated disrupted function of the Kv7.2 and Kv7.3 potassium channels due to significant reduction of cell surface expression (Orhan, G., et al. (2014)). A different variant in the same codon resulting in a change to glutamine, p.(Arg560Gln) has also been previously reported as likely pathogenic in a clinical case (ClinVar). Analysis of parental samples indicated this variant to be de novo. Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.
Institute of Human Genetics, University of Leipzig Medical Center RCV000678188 SCV001428916 pathogenic Early infantile epileptic encephalopathy 7 2017-12-19 criteria provided, single submitter clinical testing
GeneReviews RCV000678188 SCV000484637 pathogenic Early infantile epileptic encephalopathy 7 2016-03-31 no assertion criteria 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

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