Submissions for variant NM_172107.4(KCNQ2):c.1637T>C (p.Met546Thr)

dbSNP: rs886041860

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000310621	SCV000330640	pathogenic	not provided	2016-08-16	criteria provided, single submitter	clinical testing	The M546T pathogenic variant in the KCNQ2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. However, a missense variant at the same residue, M546V, has been reported in the heterozygous state in an individual with profound intellectual disability and neonatal-onset seizures showing burst suppression on EEG that resolved by age 3 years (Weckhuysen et al., 2012). In addition, functional studies of the M546V variant, denoted as M518V due to alternative nomenclature, demonstrated loss of function and altered conduction of the channel protein (Orhan et al., 2014). The M546T variant 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 M546T 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 occurs at a position that is conserved across species and is located within the C-terminal cytoplasmic domain (Singh et al., 2003; Richards et al., 2004). In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret M546T variant as a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001855072	SCV002292332	likely pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2020-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces methionine with threonine at codon 546 of the KCNQ2 protein (p.Met546Thr). The methionine residue is moderately conserved and there is a moderate physicochemical difference between methionine and threonine. 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. This variant disrupts the p.Met546 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22275249, 24318194). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This variant has not been reported in the literature in individuals with KCNQ2-related conditions. ClinVar contains an entry for this variant (Variation ID: 280703). This variant is not present in population databases (ExAC no frequency).
Revvity Omics, Revvity	RCV000310621	SCV003811975	uncertain significance	not provided	2021-04-16	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004529458	SCV004110867	uncertain significance	KCNQ2-related disorder	2023-03-21	criteria provided, single submitter	clinical testing	The KCNQ2 c.1637T>C variant is predicted to result in the amino acid substitution p.Met546Thr. 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. A different missense variant affecting the same amino acid (p. Met546Val) has been reported to have occurred de novo in an individual with epilepsy and is considered pathogenic (Weckhuysen et al. 2012. PubMed ID: 22275249, https://www.ncbi.nlm.nih.gov/clinvar/variation/39761/). The c.1637T>C (p.Met546Thr) variant has conflicting interpretations in ClinVar, including uncertain significance, likely pathogenic, and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/280703/). Although we suspect this variant may be pathogenic, at this time, the clinical significance is uncertain due to the absence of conclusive functional and genetic evidence.