ClinVar Miner

Submissions for variant NM_172107.3(KCNQ2):c.793G>A (p.Ala265Thr) (rs794727740)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000187875 SCV000231221 likely pathogenic not provided 2014-10-22 criteria provided, single submitter clinical testing
GeneDx RCV000187875 SCV000241475 pathogenic not provided 2018-12-20 criteria provided, single submitter clinical testing The A265T pathogenic variant in the KCNQ2 gene was reported as de novo in an individual with early-onset epileptic encephalopathy (EEOC) (Milh et al., 2013). It has also been identified as a de novo change in an individual with epilepsy previously tested at GeneDx. In addition, missense variants at the same and in nearby residues (A265V, A265P, G271V) have been reported in the Human Gene Mutation Database in association with KCNQ2-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. A265T 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. The A265T variant 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. This substitution alters a highly conserved position in the pore-forming loop between the 5th and 6th transmembrane domains of the protein. Therefore, the presence of A265T is consistent with the diagnosis of a KCNQ2-related disorder in this individual.
GeneReviews RCV000179032 SCV000484577 pathogenic Early infantile epileptic encephalopathy 7 2016-03-31 no assertion criteria provided literature only EE (epileptic encephalopathy)
Genetic Services Laboratory, University of Chicago RCV000192955 SCV000247667 likely pathogenic Seizures 2014-06-03 criteria provided, single submitter clinical testing
Invitae RCV000555510 SCV000634076 pathogenic Early infantile epileptic encephalopathy 2017-11-22 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 265 of the KCNQ2 protein (p.Ala265Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in multiple individuals affected with early onset epileptic encephalopathy (PMID: 23692823, 27535030, 27602407, 27779742). ClinVar contains an entry for this variant (Variation ID: 197891). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Two other missense substitutions at this codon (p.Ala265Pro and p.Ala265Val) have also been reported to be de novo in individuals affected with early onset epileptic encephalopathy (PMID: 22275249, 22926866). This suggests that the alanine residue is critical for KCNQ2 protein function. For these reasons, this variant has been classified as Pathogenic.
NeuroMeGen,Hospital Clinico Santiago de Compostela RCV000179032 SCV000258972 pathogenic Early infantile epileptic encephalopathy 7 no assertion criteria provided clinical testing

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