Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002318363 | SCV000851788 | likely pathogenic | Inborn genetic diseases | 2016-03-09 | criteria provided, single submitter | clinical testing | The p.S195F variant (also known as c.584C>T), located in coding exon 4 of the KCNQ2 gene, results from a C to T substitution at nucleotide position 584. The serine at codon 195 is replaced by phenylalanine, an amino acid with highly dissimilar properties. A different amino acid substitution located at the same codon, p.S195P, was detected as de novo in a 2 year old male who presented with seizure onset and developmental plateau at five months of age, hypotonia, swallowing difficulties, microcephaly, axial hypotonia, and intellectual disability (Weckhuysen S, et al. Neurology 2013;81(19):1697-703). The p.S195F variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6491 samples (12982 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. p.S195 is located at the extracellular end of the S4 transmembrane region in the voltage-sensing domain and may destabilize the interface with the adjacent monomer and inhibit gating of the sensing domain (Miceli F et al J. Neurosci. 2015;35(9):3782-93). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Invitae | RCV001322352 | SCV001513220 | likely pathogenic | Early infantile epileptic encephalopathy with suppression bursts | 2022-11-29 | criteria provided, single submitter | clinical testing | 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.Ser195 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24107868; Invitae). 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. ClinVar contains an entry for this variant (Variation ID: 590184). This variant has not been reported in the literature in individuals affected with KCNQ2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 195 of the KCNQ2 protein (p.Ser195Phe). |