Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000479158 | SCV000569898 | likely pathogenic | not provided | 2016-08-25 | criteria provided, single submitter | clinical testing | A D479N variant that is likely pathogenic has been identified in the PCDH19 gene. The D479N 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 6,300 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 D479N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Additionally, 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. Additionally, targeted parental test results indicate the D479N variant is apparently de novo. Therefore, we now interpret D479N as a likely pathogenic variant; however, the possibility that it is benign cannot be excluded |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002509405 | SCV002819897 | uncertain significance | not specified | 2022-12-29 | criteria provided, single submitter | clinical testing | Variant summary: PCDH19 c.1435G>A (p.Asp479Asn) results in a conservative amino acid change located in the Cadherin-like domain (IPR002126) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 181524 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1435G>A has been reported in the literature as a de-novo variant in cis with another de-novo variant c.1372C>T (p.Y458H) in at-least one individual affected with features of PCDH19-related Developmental And Epileptic Encephalopathy, 9 (example, Smith_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |