Submissions for variant NM_001184880.2(PCDH19):c.707C>G (p.Pro236Arg)

dbSNP: rs1060502176

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000476281	SCV000548731	pathogenic	Developmental and epileptic encephalopathy, 9	2022-09-17	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This missense change has been observed in individual(s) with clinical features of early infantile epileptic encephalopathy (PMID: 31487502; Invitae). In at least one individual the variant was observed to be de novo. This variant disrupts the p.Pro236 amino acid residue in PCDH19. Other variant(s) that disrupt this residue have been observed in individuals with PCDH19-related conditions (PMID: 21480887, 26993267), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 408904). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 236 of the PCDH19 protein (p.Pro236Arg).
GeneDx	RCV000480604	SCV000570657	likely pathogenic	not provided	2016-09-01	criteria provided, single submitter	clinical testing	The P236R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant 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 P236R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size, and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Two different missense variants in the same codon (P236S, P236L) as well as missense variants in nearby residues (N232S, N234S) have been reported in the Human Gene Mutation Database in association with PCDH19-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Additionally, targeted parental test results indicate the P236R variant is apparently de novo in this individual. Therefore, we now interpret P236R as a likely pathogenic variant; however, the possibility that it is benign cannot be excluded.