Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000498715 | SCV000589539 | likely pathogenic | not provided | 2015-11-01 | criteria provided, single submitter | clinical testing | The H328N variant in the KCNQ2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The H328N 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 H328N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (H324R, R325G, R333W, R333Q) have been reported in the Human Gene Mutation Database in association with epilepsy and epileptic encephalopathy (Stenson et al., 2014), supporting the functional importance of this region of the protein. The H328N variant is a strong candidate for a pathogenic variant however, the possibility it may be a rare benign variant cannot be excluded. |
| Invitae | RCV001366644 | SCV001562953 | uncertain significance | Early infantile epileptic encephalopathy with suppression bursts | 2020-08-20 | criteria provided, single submitter | clinical testing | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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: 431951). This variant is not present in population databases (ExAC no frequency). This sequence change replaces histidine with asparagine at codon 328 of the KCNQ2 protein (p.His328Asn). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and asparagine. |