ClinVar Miner

Submissions for variant NM_172107.4(KCNQ2):c.637C>T (p.Arg213Trp) (rs118192203)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000187866 SCV000230473 pathogenic not provided 2015-02-18 criteria provided, single submitter clinical testing
GeneDx RCV000187866 SCV000241466 pathogenic not provided 2018-12-11 criteria provided, single submitter clinical testing A published disease-causing variant has been identified in the KCNQ2 gene. The R213W missense variant in the KCNQ2 gene has been previously reported in two Japanese siblings with benign familial neonatal convulsions (BFNC)(Sadewa et al., 2008). Neither parent was found to have the R213W variant, and after the relationships among the relatives was confirmed with parentage testing, germ-line mosaicism in one of the parents is suspected (Sadewa et al., 2008). Functional studies revealed that R213W decreases the stability of the ion channel and decreased voltage sensitivity (Miceli et al., 2013). R213W 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. R213W 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. It alters highly conserved position in the S4 voltage-sensing domain of the KCNQ2 protein.
Invitae RCV000234346 SCV000291572 likely pathogenic Early infantile epileptic encephalopathy 2019-02-22 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 213 of the KCNQ2 protein (p.Arg213Trp). The arginine residue is highly 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 observed to segregate with benign familial neonatal seizures in one family (PMID: 18353052). This variant has been reported to affect KCNQ2 protein function (PMID: 23440208). This variant disrupts the p.Arg213 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been observed in individuals with KCNQ2-related conditions (PMID: 22275249, 25982755), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000178400 SCV000700169 pathogenic Early infantile epileptic encephalopathy 7 2017-02-02 criteria provided, single submitter clinical testing
Mendelics RCV000990336 SCV001141279 pathogenic Benign familial neonatal seizures 1 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000187866 SCV001249239 pathogenic not provided 2018-11-01 criteria provided, single submitter clinical testing
GeneReviews RCV000178400 SCV000041649 pathogenic Early infantile epileptic encephalopathy 7 2016-03-31 no assertion criteria provided literature only BFNE (benign familial neonatal epilepsy), EE (epileptic encephalopathy)

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