ClinVar Miner

Submissions for variant NM_172107.4(KCNQ2):c.701C>T (p.Thr234Ile)

dbSNP: rs794727741
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000193491 SCV000247665 likely pathogenic Seizure 2014-12-05 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001235310 SCV001407989 pathogenic Early infantile epileptic encephalopathy with suppression bursts 2023-10-29 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 234 of the KCNQ2 protein (p.Thr234Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of epilepsy (PMID: 29056246, 29720203; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 197892). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNQ2 protein function with a positive predictive value of 95%. This variant disrupts the p.Thr234 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been observed in individuals with KCNQ2-related conditions (PMID: 25818041; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000179033 SCV005327124 likely pathogenic not provided 2023-12-16 criteria provided, single submitter clinical testing Reported in an individual with seizures and developmental delay, though parental segregation was not included (PMID: 29056246); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This substitution is predicted to be within the transmembrane segment S5; Missense variants in this gene are often considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25818041, 29720203, 29056246)
Eurofins Ntd Llc (ga) RCV000179033 SCV000231222 uncertain significance not provided 2014-06-27 flagged submission clinical testing

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