Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000521156 | SCV000617392 | likely pathogenic | not provided | 2017-07-18 | criteria provided, single submitter | clinical testing | The P567L variant in the PCDH19 gene has been reported previously in several females with epilepsy and intellectual disability, including at least one family where the variant was inherited from an asymptomatic mother and at least one family where the variant was apparently de novo (Depienne et al., 2011; Marini et al., 2012; Cappelletti et al., 2015). The P567L variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P567L 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, but in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret P567L as a likely pathogenic variant. |
| Fulgent Genetics, |
RCV000763636 | SCV000894506 | pathogenic | Developmental and epileptic encephalopathy, 9 | 2018-10-31 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000763636 | SCV001488071 | pathogenic | Developmental and epileptic encephalopathy, 9 | 2022-06-17 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 567 of the PCDH19 protein (p.Pro567Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with PCDH19-related conditions (PMID: 21053371, 30530412). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 449356). 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 not expected to disrupt PCDH19 protein function. Experimental studies have shown that this missense change affects PCDH19 function (PMID: 34082468). For these reasons, this variant has been classified as Pathogenic. |