Submissions for variant NM_001184880.2(PCDH19):c.369C>A (p.Asn123Lys)

dbSNP: rs796052796

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188346	SCV000241958	likely pathogenic	not provided	2014-03-20	criteria provided, single submitter	clinical testing	This variant is denoted p.Asn123Lys (AAC>AAA): c.369 C>A in exon 1 of the PCDH19 gene (NM_001105243.1). The N123K variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The N123K 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 highly conserved across species, and another nearby missense mutation (D121N) has been reported in association with epileptic encephalopathy, supporting the functional importance of this region of the protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in INFANT-EPI panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV003621514	SCV004551797	pathogenic	Developmental and epileptic encephalopathy, 9	2023-10-29	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 123 of the PCDH19 protein (p.Asn123Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of developmental and epileptic encephalopathy (PMID: 29655203, 35571021; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 206310). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.