Submissions for variant NM_001184880.2(PCDH19):c.298A>T (p.Ile100Phe)

gnomAD frequency: 0.00001  dbSNP: rs796052838

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188400	SCV000242012	uncertain significance	not provided	2014-12-11	criteria provided, single submitter	clinical testing	This variant is denoted p.Ile100Phe (ATC>TTC): c.298 A>T in exon 1 of the PCDH19 gene (NM_001105243.1). The I100F 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 I100F variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved through mammals, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CHILD-EPIV2-1 panel(s).
Invitae	RCV001857630	SCV002209515	uncertain significance	Developmental and epileptic encephalopathy, 9	2022-08-23	criteria provided, single submitter	clinical testing	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. 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 not expected to disrupt PCDH19 protein function. ClinVar contains an entry for this variant (Variation ID: 206363). This variant has not been reported in the literature in individuals affected with PCDH19-related conditions. This variant is present in population databases (rs796052838, gnomAD 0.01%). This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 100 of the PCDH19 protein (p.Ile100Phe).