ClinVar Miner

Submissions for variant NM_172107.4(KCNQ2):c.910_912TTC[1] (p.Phe305del) (rs118192212)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory,University of Chicago RCV000194164 SCV000247668 pathogenic Seizures 2015-06-26 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000234792 SCV000291976 pathogenic Early infantile epileptic encephalopathy 7 2016-06-09 criteria provided, single submitter research
GeneDx RCV000414259 SCV000491167 pathogenic not provided 2017-05-22 criteria provided, single submitter clinical testing The c.913_915delTTC pathogenic variant has been identified in the KCNQ2 gene. The c.913_915delTTC variant was initially reported as a confirmed de novo variant in a child reported to have normal development and a history of neonatal-onset tonic and tonic-clonic seizures that resolved by six months of age (Ishii et al., 2009). The c.913_915delTTC variant was also reported as an assumed de novo variant in identical twins with neonatal epileptic encephalopathy with a burst suppression pattern on EEG, profound developmental delay, and spasticity (Millichap et al., 2016). In vitro functional studies indicate that the c.913_915delTTC variant significantly impairs potassium channel function (Ishii et al., 2009). The c.913_915delTTC variant results in an in-frame deletion of one amino acid, denoted p.Phe305del. However, the c.913_915delTTC variant is not predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. The c.913_915delTTC variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Furthermore, this deletion occurs at a conserved position predicted to be within the transmembrane segment S6. Therefore, the presence of c.913_915delTTC is consistent with the diagnosis of a KCNQ2-related disorder in this individual.
Mendelics RCV000990332 SCV001141275 benign Benign familial neonatal seizures 1 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001002283 SCV001160166 pathogenic not specified 2018-12-15 criteria provided, single submitter clinical testing De novo occurrence of the p.Phe305del variant has been reported in several individuals (Ishii 2009, Millichap 2016, Sterbova 2017, Bowling 2017, Spagnoli 2018) including identical twins (Millichap 2016). This variant is absent from general population databases including gnomAD but is listed in ClinVar with pathogenic classification (ClinVar ID 211236). The p.Phe305del variant is located in the Kv7.2 channel transmembrane segment 6, in the ion transport domain (IPR005821). Ishii et al. (2009) showed that this variant (reported as Phe304del) leads to null function with no current observed in the mutant KCNQ2 potassium channel. Based on the available evidence, this de novo p.Phe305del KCNQ2 gene variant was classified as pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000414259 SCV001247382 pathogenic not provided 2016-09-01 criteria provided, single submitter clinical testing
GeneReviews RCV000678098 SCV000041663 pathogenic Benign Rolandic epilepsy 2016-03-31 no assertion criteria provided literature only BECTS (benign childhood epilepsy with centrotemporal spikes)
Section for Clinical Neurogenetics,University of Tübingen RCV000234792 SCV001156087 likely pathogenic Early infantile epileptic encephalopathy 7 2019-08-01 no assertion criteria provided research

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