Submissions for variant NM_001184880.2(PCDH19):c.1352C>T (p.Pro451Leu)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003041460	SCV003445292	uncertain significance	Developmental and epileptic encephalopathy, 9	2022-07-09	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 451 of the PCDH19 protein (p.Pro451Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of PCDH19-related conditions (PMID: 26765483). 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.Pro451 amino acid residue in PCDH19. Other variant(s) that disrupt this residue have been observed in individuals with PCDH19-related conditions (PMID: 33262389), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV005235680	SCV005882025	pathogenic	not provided	2024-09-09	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: 30451291, 26765483, 32852734)