Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000255035 | SCV000322289 | pathogenic | not provided | 2018-04-04 | criteria provided, single submitter | clinical testing | The D203N pathogenic variant in the PLP1 gene has been reported previously, using alternate nomenclature D202N, in a male with Pelizaeus-Merzbacher disease (Mimault et al., 1999). Functional studies show D203N is retained in the endoplasmic reticulum and forms fewer crosslinks between PLP and DM20, with the authors concluding that D203N disrupts the formation of a disulfide bridge in PLP/DM20 that is required for normal protein folding and trafficking (Dhaunchak and Nave, 2007; Dhaunchak et al., 2011). The D203N variant was not observed in approximately 6,500 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 D203N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. We interpret D203N as a pathogenic variant. |
| Illumina Laboratory Services, |
RCV003985083 | SCV004801490 | pathogenic | Pelizaeus-Merzbacher disease | 2018-03-07 | criteria provided, single submitter | clinical testing | The PLP1 c.607G>A p.(Asp203Asn) missense variant , also known as p.(Asp202Asn), has been previously reported in one study where it was identified in one affected male with Pelizaeus-Merzbacher disease (PMD) (Mimault et al. 1999). Additionally, at least four other missense variants resulting in alternate amino acid changes at the 203 residue have been identified in individuals with PMD in the literature (Doll et al. 1992, Nagao et al. 1998, Mimault et al. 1999, Cailloux et al. 2000). This variant is not observed in version 2.1.1 of the Genome Aggregation Database. Expression of the p.(Asp203Asn) variant in various cell lines, including oli-neu, an oligodendrocyte cell line, revealed retention of the PLP1 protein in the endoplasmic reticulum (ER), which were rescued by cysteine to serine substitutions in the neighboring residues. It is postulated that p.(Asp203Asn) variant in the large extracellular loop 2 of the protein, induces minor structural changes that prevent efficient formation of normal disulfide bridges, which exposes unpaired cysteines in the oxidative environment of the ER and competing oxidations generate aberrant PLP dimers that fail to mature into oligomeric forms and are retained in the ER (Dhaunchak and Nave 2007, Dhaunchak et al. 2011). Based on the collective evidence, the c.607G>A p.(Asp203Asn) variant is classified as pathogenic for Pelizaeus-Merzbacher disease. |