CMTDIE

Genetic Context

HGNC-Approved Gene Symbol

INF2

Gene Full Name

Inverted Formin 2

Chromosome

14q32.33

Zygosity of Responsible Variant

Heterozygous

Mitochondrial Involvement

Yes

Variant Mechanism

Toxic Gain of Function (GoF)

Details

Mechanistic basis:
Overactivity

Confidence:
Medium

Prediction:
The literature predicts a gain-of-function mechanism for CMTDIE: the dominant missense variants cluster in the N-terminal diaphanous-inhibitory domain and disrupt the intramolecular DID-DAD interaction that keeps INF2 autoinhibited, releasing the formin into dysregulated constitutive actin polymerization. Because the mutant does more of INF2's normal activity on its own rather than disrupting the wild-type, the evidence supports overactivity over haploinsufficiency or a dominant-negative effect, at medium confidence on limited mechanistic data.

Rationale:
Dominant N-terminal DID missense alleles disrupt the intramolecular DID-DAD autoinhibitory clamp and release INF2 to over-do its normal actin-polymerizing activity rather than disrupting the wild-type, a gain-of-function overactivity. Because a dominant-negative or interference effect on dimers is not fully excluded, confidence holds at medium.

ClinVar Pathogenic Variants

View CMTDIE ClinVar Variants

ClinGen Curation

View INF2 ClinGen Curation

CMTDIE OMIM Entry

CMTDIE OMIM

INF2 OMIM Entry

INF2 OMIM