Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000481592 | SCV000568499 | likely pathogenic | not provided | 2017-02-02 | criteria provided, single submitter | clinical testing | The C33Y variant in the PLP1 gene has been reported previously as a pathogenic variant in a male patient with a severe phenotype of Pelizaeus-Merzbacher disease (Hübner et al., 2005). This variant was not observed in approximately 6500 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 C33Y 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. Missense variants in nearby residues (G28V, A30P, A30E, L31R, L31P, F32V, F32L, C35R, C35Y) have been reported in the Human Gene Mutation Database in association with Pelizaeus-Merzbacher disease (Stenson et al., 2014), supporting the functional importance of this region of the protein. The C33Y variant is a strong candidate for a pathogenic variant, however, the possibility it may be a rare benign variant cannot be excluded. |