ClinVar Miner

Submissions for variant NM_001184880.2(PCDH19):c.707C>G (p.Pro236Arg) (rs1060502176)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000476281 SCV000548731 uncertain significance Early infantile epileptic encephalopathy 9 2019-05-01 criteria provided, single submitter clinical testing This sequence change replaces proline with arginine at codon 236 of the PCDH19 protein (p.Pro236Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with clinical features of early infantile epileptic encephalopathy (Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. 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 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.

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