ClinVar Miner

Submissions for variant NM_172107.4(KCNQ2):c.881C>T (p.Ala294Val) (rs118192211)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000187883 SCV000610764 pathogenic not provided 2017-03-28 criteria provided, single submitter clinical testing
GeneDx RCV000187883 SCV000241485 pathogenic not provided 2018-04-27 criteria provided, single submitter clinical testing The A294V variant in the KCNQ2 gene has been reported previously as a de novo pathogenic variant in multiple unrelated individuals with early-onset epileptic encephalopathy (Milh et al., 2013; Kato et al., 2013, Allen et al., 2014). Additionally, the A294V variant has been observed as a de novo variant with confirmed parentage in a patient previously tested at GeneDx, and has been reported as a de novo variant in patients reported in other databases including ClinVar and LOVD. Functional studies of A294V indicate that the variant alters protein expression and function (Abidi et al., 2015). The A294V variant is not observed in large population cohorts (Lek et al., 2016). The A294V variant is a conservative amino acid substitution; however, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. A different pathogenic missense variant at the same position (A294G) and other variants nearby residues have been reported in individuals with KCNQ2-related disorders (Steinlein et al., 2007; Stenson et al., 2014). Therefore, the presence of A294V is consistent with the diagnosis of a KCNQ2-related disorder in this individual.
GeneReviews RCV000203604 SCV000484590 pathogenic Early infantile epileptic encephalopathy 7 2016-03-31 no assertion criteria provided literature only EE (epileptic encephalopathy)
Invitae RCV000473067 SCV000543200 pathogenic Early infantile epileptic encephalopathy 2016-12-19 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 294 of the KCNQ2 protein (p.Ala294Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been shown to arise de novo in many (>10) individuals affected with early-onset epileptic encephalopathy (PMID: 23692823, 26007637, 25052858, 25880994, 27602407). ClinVar contains an entry for this variant (Variation ID: 205886). Experimental studies in cultured neuronal cells have shown that this missense change leads to cellular mislocalization of the KCNQ2 protein (PMID: 26007637, 27905566). This variant identified in the KCNQ2 gene is located in the transmembrane S6 region of the resulting protein (PMID: 25348405). For these reasons, this variant has been classified as Pathogenic.
NeuroMeGen,Hospital Clinico Santiago de Compostela RCV000203604 SCV000258966 pathogenic Early infantile epileptic encephalopathy 7 criteria provided, single submitter clinical testing
Neurogenetics Laboratory - MEYER,AOU Meyer RCV000417034 SCV000494522 pathogenic Epileptic encephalopathy 2016-11-16 criteria provided, single submitter clinical testing

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