HSAN-1C

Genetic Context

HGNC-Approved Gene Symbol

SPTLC2

Gene Full Name

serine palmitoyltransferase long chain base subunit 2

Chromosome

14q24.3

Zygosity of Responsible Variant

Heterozygous

Variant Mechanism

Toxic Gain of Function (GoF)

Details

Mechanistic basis:
Neomorphic

Confidence:
High

Prediction:
Across HSAN-1C the reported evidence predicts a gain of new activity rather than loss of the old: dominant SPTLC2 missense alleles redirect serine palmitoyltransferase onto alanine and glycine, and the resulting 1-deoxysphingolipids lack the C1 hydroxyl group that normal sphingoid bases carry. Without it they can neither be built into complex sphingolipids nor cleared through the canonical degradation route, so they persist, and sensory neurons exposed to them retract and lose neurites. The toxicity belongs to the metabolite, not to any shortfall in SPT activity.

Rationale:
Because 1-deoxysphingolipids cannot enter the normal catabolic pathway, dorsal root ganglion neurons carry a lipid they have no route to dispose of, and the longest sensory axons show it first. Supplying more normal enzyme adds canonical product but removes none of the atypical one, which is why the evidence reads as acquired toxicity rather than haploinsufficiency.

ClinVar Pathogenic Variants

View SPTLC2 ClinVar Variants

ClinGen Curation

View SPTLC2 ClinGen Curation

HSAN-1C OMIM Entry

HSAN-1C OMIM

SPTLC2 OMIM Entry

SPTLC2 OMIM