ClinVar Miner

Submissions for variant NM_172107.3(KCNQ2):c.821C>T (p.Thr274Met) (rs727503974)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000153394 SCV000202887 pathogenic not provided 2018-04-18 criteria provided, single submitter clinical testing
GeneDx RCV000153394 SCV000241481 pathogenic not provided 2016-10-20 criteria provided, single submitter clinical testing A published pathogenic has been identified in the KCNQ2 gene. The T274M variant was previously identified in a patient with neonatal epileptic encephalopathy and a burst suppression pattern on EEG and was not detected in 276 ethnically matched controls (Weckhuysen et al., 2012). Functional studies have demonstrated that the T274M variant results reduced protein function (Orhan et al., 2014). The T247M variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T274M 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. T274M alters a conserved position predicted to be within the pore forming loop between the S5 and S6 segments of the transmembrane domain, and other pathogenic variants in this region of the protein have been reported in association with epileptic encephalopathy and benign familial neonatal seizures (Weckhuysen et al., 2012; Richards et al., 2004). Therefore, the presence of T274M is consistent with the diagnosis of a KCNQ2-related disorder in this individual.
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000203603 SCV000537720 pathogenic Early infantile epileptic encephalopathy 7 2014-08-11 criteria provided, single submitter clinical testing
Invitae RCV000636323 SCV000757762 pathogenic Early infantile epileptic encephalopathy 2017-11-13 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 274 of the KCNQ2 protein (p.Thr274Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with early infantile epileptic encephalopathy, and at least 3 of them arose de novo (PMID: 22275249, 27535030, 27779742, 28133863). ClinVar contains an entry for this variant (Variation ID: 167208). Experimental studies have shown that this missense change caused a dominant-negative reduction of the resulting potassium current at subthreshold membrane potentials (PMID: 24318194). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics Inc RCV000153394 SCV000842507 pathogenic not provided 2018-02-28 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000203603 SCV000993616 pathogenic Early infantile epileptic encephalopathy 7 2019-03-19 criteria provided, single submitter research
NeuroMeGen,Hospital Clinico Santiago de Compostela RCV000203603 SCV000258974 pathogenic Early infantile epileptic encephalopathy 7 no assertion criteria provided clinical testing
GeneReviews RCV000203603 SCV000484581 pathogenic Early infantile epileptic encephalopathy 7 2016-03-31 no assertion criteria provided literature only EE (epileptic encephalopathy)

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