CMTDIB

Genetic Context

HGNC-Approved Gene Symbol

DNM2

Gene Full Name

dynamin 2

Chromosome

19p13.2

Zygosity of Responsible Variant

Heterozygous

Variant Mechanism

Toxic Gain of Function (GoF)

Details

Mechanistic basis:
Overactivity

Confidence:
Medium

Prediction:
The literature predicts an overactivity gain-of-function mechanism for CMTDIB: PH-domain changes in DNM2 yield a dynamin-2 that self-assembles more readily and carries elevated assembly-stimulated GTPase activity, so endocytic membrane fission runs faster and less selectively than the cell can regulate. That excess is intrinsic to the mutant and does not require the wild-type partner, and a single null DNM2 allele does not reproduce the phenotype. Whether the dominant effect is purely overactivity or also involves mixed dynamin polymers is argued, so confidence is medium.

Rationale:
Faster and more avid self-assembly means the mutant dynamin fissions membranes on its own account, so the trafficking defect follows from surplus activity rather than from any block imposed on normal dynamin-2. Hyperassembling DNM2 alleles produce dominant centronuclear myopathy by the same overactive route, reinforcing that reading. How much of the effect persists once mutant and wild-type co-assemble is the open question behind the medium grade.

ClinVar Pathogenic Variants

View DNM2 ClinVar Variants

ClinGen Curation

View DNM2 ClinGen Curation

CMTDIB OMIM Entry

CMTDIB OMIM

DNM2 OMIM Entry

DNM2 OMIM