Submissions for variant NM_001184880.2(PCDH19):c.1342G>A (p.Asp448Asn)

dbSNP: rs1569314809

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001231311	SCV001403828	pathogenic	Developmental and epileptic encephalopathy, 9	2022-11-21	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with clinical features of PCDH19-related conditions (PMID: 33262389). In at least one individual the variant was observed to be de novo. This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 448 of the PCDH19 protein (p.Asp448Asn). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 958194). 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. This variant disrupts the p.Asp448 amino acid residue in PCDH19. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). 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.
GeneDx	RCV004727015	SCV005332401	likely pathogenic	not provided	2024-03-19	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29377098, 33262389)