SMA-LEP-2B

Genetic Context

HGNC-Approved Gene Symbol

BICD2

Gene Full Name

BICD cargo adaptor 2

Chromosome

9q22.31

Zygosity of Responsible Variant

Heterozygous

Variant Mechanism

Toxic Gain of Function (GoF)

Details

Mechanistic basis:
Overactivity

Confidence:
Medium

Prediction:
Reported evidence predicts overactivity rather than loss in SMA-LEP-2B: the congenital presentation, with arthrogryposis, contractures and respiratory compromise present at birth, arises from BICD2 substitutions that hold the adaptor in an activated conformation and remodel its interactome around Rab6 and the dynein-dynactin motor. Golgi-derived cargo transport is driven rather than blunted. Severity across BICD2 families tracks which substitution is present rather than how much adaptor remains, a distribution that fits activating alleles.

Rationale:
Severity tracks the substitution, not the dose: truncating BICD2 alleles are not an established cause of this phenotype, while particular missense substitutions recur at its most severe end. What remains argued is how much of the transport defect comes from excess motor activation and how much from an altered cargo interactome.

ClinVar Pathogenic Variants

View BICD2 ClinVar Variants

SMA-LEP-2B OMIM Entry

SMA-LEP-2B OMIM

BICD2 OMIM Entry

BICD2 OMIM