Submissions for variant NM_001184880.2(PCDH19):c.707C>T (p.Pro236Leu)

dbSNP: rs1060502176

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000768278	SCV000898866	likely pathogenic	Developmental and epileptic encephalopathy, 9	2021-03-30	criteria provided, single submitter	clinical testing	PCDH19 NM_001184880.1 exon 1 p.Pro236Leu (c.707C>T): This variant has been reported in the literature as de novo in 1 individual with early infantile epileptic encephalopthy (Trump 2016 PMID:26993267). This variant is not present in large control databases. Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Of note, an additional variant at this codon (p.Pro236Ser) has been reported as de novo and in association with disease, supporting that this region has signifiance. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000768278	SCV002239454	pathogenic	Developmental and epileptic encephalopathy, 9	2024-10-22	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 236 of the PCDH19 protein (p.Pro236Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early infantile epileptic encephalopathy (PMID: 26993267). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 626145). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PCDH19 protein function with a positive predictive value of 95%. This variant disrupts the p.Pro236 amino acid residue in PCDH19. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 31487502; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	RCV000768278	SCV004037124	likely pathogenic	Developmental and epileptic encephalopathy, 9		criteria provided, single submitter	not provided
Centre for Inherited Metabolic Diseases, Karolinska University Hospital	RCV000768278	SCV004697506	pathogenic	Developmental and epileptic encephalopathy, 9	2024-02-27	criteria provided, single submitter	clinical testing