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:
The literature predicts a neomorphic gain-of-function mechanism for HSAN-1C: dominant SPTLC2 missense mutations alter serine palmitoyltransferase substrate specificity so it uses alanine and glycine instead of serine, generating neurotoxic 1-deoxysphingolipids. This is a novel toxic species rather than loss of enzyme activity, and added wild-type SPT does not clear the toxic metabolites, consistent with acquired toxic activity rather than haploinsufficiency or a dominant-negative effect.

Rationale:
Dominant SPTLC2 missense alleles shift SPT substrate specificity toward alanine and glycine, generating neurotoxic 1-deoxysphingolipids that wild-type enzyme cannot clear, consistent with an acquired toxic activity rather than haploinsufficiency or dominant-negative interference: a neomorphic gain of function.

ClinVar Pathogenic Variants

View HSAN-1C ClinVar Variants

ClinGen Curation

View SPTLC2 ClinGen Curation

HSAN-1C OMIM Entry

HSAN-1C OMIM

SPTLC2 OMIM Entry

SPTLC2 OMIM