HMSN-6B

Genetic Context

HGNC-Approved Gene Symbol

SLC25A46

Gene Full Name

solute carrier family 25 member 46

Chromosome

5q22.1

Zygosity of Responsible Variant

Homozygous or Compound Heterozygous

Mitochondrial Involvement

Yes

Variant Mechanism

Loss of Function (LoF)

Details

Mechanistic basis:
Hypomorphic

Confidence:
High

Prediction:
Protein-level data predict biallelic loss of function in HMSN-6B: SLC25A46 is an outer mitochondrial membrane protein related to the fusion machinery, working alongside MFN2 and the MICOS complex to balance mitochondrial fission against fusion and to maintain membrane contacts. Pathogenic missense variants destabilize the protein and truncating alleles remove it, and how much protein remains at steady state predicts where a family sits on a spectrum running from CMT with optic atrophy to lethal congenital pontocerebellar hypoplasia.

Rationale:
Steady-state abundance is the variable that matters: mutant SLC25A46 is degraded rapidly, and the severity gradient across families follows how much survives rather than which residue changed. Optic atrophy joins the peripheral disease because retinal ganglion cells share the dependence on mitochondrial dynamics that MFN2 and OPA1 disease demonstrates.

ClinVar Pathogenic Variants

View SLC25A46 ClinVar Variants

ClinGen Curation

View SLC25A46 ClinGen Curation

HMSN-6B OMIM Entry

HMSN-6B OMIM

SLC25A46 OMIM Entry

SLC25A46 OMIM