Submissions for variant NM_001184880.2(PCDH19):c.1031C>T (p.Pro344Leu)

dbSNP: rs796052811

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188363	SCV000241975	pathogenic	not provided	2014-07-31	criteria provided, single submitter	clinical testing	This variant is denoted p.Pro344Leu (CCG>CTG): c.1031 C>T in exon 1 of the PCDH19 gene (NM_001105243.1). The P344L missense substitution in the PCDH19 gene has been reported previously as a de novo mutation in a female patient with epilepsy, moderate intellectual disability, aggression, and autistic features (van Harssel et al., 2013). It 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. This substitution alters a highly conserved position in the predicted cadherin 3 domain of the PCDH19 protein where other missense mutations, including a different substitution at the same codon (P344R), have been reported in association with a PCDH19-related disorder. Therefore, P344L is considered a pathogenic mutation, and its presence is consistent with a diagnosis of a PCDH19-related disorder. The variant is found in EPILEPSY panel(s).
CeGaT Center for Human Genetics Tuebingen	RCV000188363	SCV001249613	pathogenic	not provided	2019-01-01	criteria provided, single submitter	clinical testing
Invitae	RCV002514025	SCV003445094	pathogenic	Developmental and epileptic encephalopathy, 9	2022-07-05	criteria provided, single submitter	clinical testing	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. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 206326). This missense change has been observed in individual(s) with clinical features of PCDH19-related conditions (PMID: 23334464). 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 proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 344 of the PCDH19 protein (p.Pro344Leu).