Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000494296 | SCV000582419 | likely pathogenic | not provided | 2015-09-11 | criteria provided, single submitter | clinical testing | The N123K variant has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,400 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 N123K 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. Additionally, a missense variant in a nearby residue (D121N) have been reported in the Human Gene Mutation Database in association with epileptic encephalopathy (Stenson et al., 2014). Therefore, the N123K variant is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded. |
| Labcorp Genetics |
RCV002524035 | SCV003473374 | pathogenic | Developmental and epileptic encephalopathy, 9 | 2022-09-12 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. 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 PCDH19 protein function. ClinVar contains an entry for this variant (Variation ID: 429767). This missense change has been observed in individual(s) with clinical features of PCDH19-related conditions (PMID: 29655203; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 123 of the PCDH19 protein (p.Asn123Lys). |