Submissions for variant NM_172107.4(KCNQ2):c.1076C>T (p.Thr359Met)

dbSNP: rs118192219

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, University of Leipzig Medical Center	RCV001253596	SCV001429398	pathogenic	Seizures, benign familial neonatal, 1	2021-08-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001295143	SCV001484056	likely pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2024-10-21	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 359 of the KCNQ2 protein (p.Thr359Met). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with KCNQ2-related conditions. ClinVar contains an entry for this variant (Variation ID: 976330). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt KCNQ2 protein function with a positive predictive value of 95%. This variant disrupts the p.Thr359 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19559753; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx	RCV001587291	SCV001816242	likely pathogenic	not provided	2021-05-12	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
PreventionGenetics, part of Exact Sciences	RCV004538537	SCV004121074	uncertain significance	KCNQ2-related disorder	2022-10-13	criteria provided, single submitter	clinical testing	The KCNQ2 c.1076C>T variant is predicted to result in the amino acid substitution p.Thr359Met. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating it is rare. KCNQ2 is generally intolerant to missense variation (http://gnomad.broadinstitute.org), and different missense variants affecting the same amino acid have been reported in association with seizure disorders (p.Thr359Lys, Volkers L et al 2009. PubMed ID: 19559753; p.Thr359Ala, Lindy et al. 2018. PubMed ID: 29655203, Table S4). Taken together, although we suspect that the c.1076C>T (p.Thr359Met) variant may be pathogenic, at this time, the clinical significance is uncertain due to the absence of conclusive functional and genetic evidence.