ClinVar Miner

Submissions for variant NM_172107.3(KCNQ2):c.917C>T (p.Ala306Val) (rs864321707)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics,Fulgent Genetics RCV000763451 SCV000894227 pathogenic Benign familial neonatal seizures 1; Early infantile epileptic encephalopathy 7 2018-10-31 criteria provided, single submitter clinical testing
GeneReviews RCV000203598 SCV000484595 pathogenic Early infantile epileptic encephalopathy 7 2016-03-31 no assertion criteria provided literature only EE (epileptic encephalopathy)
Invitae RCV000545675 SCV000634081 likely pathogenic Early infantile epileptic encephalopathy 2017-05-16 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 306 of the KCNQ2 protein (p.Ala306Val). 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 reported in individuals affected with early onset epileptic encephalopathy and Ohtahara Syndrome (PMID:  26704558, 25959266, 27535030). In one of these individuals this variant was shown to arise de novo (PMID: 27535030). Clinvar contains an entry for this variant (Variation ID: 219235). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. A different missense substitution at this codon (p.Ala306Thr) has been determined to be pathogenic (PMID: 19453707, 26138355, 9425895). This suggests that the alanine residue is critical for KCNQ2 protein function and that other missense substitutions at this position may also be pathogenic. In summary, this variant is a rare missense change that has been reported in multiple affected individuals and occurs at a residue that may be functionally important. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
NeuroMeGen,Hospital Clinico Santiago de Compostela RCV000203598 SCV000258968 pathogenic Early infantile epileptic encephalopathy 7 no assertion criteria provided clinical testing

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