Hereditary Neuropathy_CMT - isolated

Gene: PMP2

I don't know

ClinGen curation:
PMP2 was first reported in relation to autosomal dominant Charcot-Marie-Tooth Disease in 2015 (Gonzaga-Jauregui et al., PMID: 26257172). At least six variants (e.g. missense, in-frame indel) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, limited segregation data, and experimental data. Variants in this gene have been reported in at least eight probands in six publications (PMIDs: 26257172, 27009151, 30249361, 31412900, 26828946, 32277537). Variants in this gene segregated with disease in several additional family members, however the lack of significant segregation in a single family yields no scorable segregation evidence. The mechanism for disease is suspected to be a monoallelic gain-of-function or dominant negative effect with variants affecting the myelin structure or causing upregulation of the protein (PMID: 28747762). This gene-disease association is additionally supported by PMP2's function in lipid homeostasis and remyelination, as well as functional evidence in PMP2 null mice. Expression of PMP2 in myelin, interacting with MPZ, a protein also associated with demyelinating CMT, also provides evidence towards its pathogenicity. A transgenic mouse model expressing the I43N variant does recapitulate many of the phenotypes observed in humans. However, the possibility for interference via overexpression, rather than from the variant itself, requires more clarification in future studies. In summary, there is limited evidence to support this gene-disease relationship.

Created: 19 Apr 2024, 4:57 a.m. | Last Modified: 19 Apr 2024, 4:57 a.m.

Panel Version: 1.44

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Charcot-Marie-Tooth disease MONDO:0015626

Publications

• 26257172
• 27009151
• 30249361
• 31412900
• 26828946
• 32277537

I don't know

On 22/03/2021, ClinGen Classified this gene-disease association as LIMITED due to the lack of evidence (CCID:005836).

The mechanism for disease is suspected to be a monoallelic gain-of-function or dominant negative effect (PMID: 28747762)

Created: 9 Apr 2024, 12:45 a.m. | Last Modified: 9 Apr 2024, 12:45 a.m.

Panel Version: 1.39

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Charcot-Marie-Tooth disease MONDO:0015626

Publications

• PMID: 28747762
• https://search.clinicalgenome.org/CCID:005836

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

Green List (high evidence)

4 unrelated families reported with missense variants, with supporting transgenic mouse and null zebrafish models.

Created: 16 Jun 2020, 6:15 a.m. | Last Modified: 16 Jun 2020, 6:15 a.m.

Panel Version: 0.46

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Charcot-Marie-Tooth disease, demyelinating, type 1G MIM#618279

Publications

• 26257172
• 26828946
• 27009151