HSAN-7

Genetic Context

HGNC-Approved Gene Symbol

SCN11A

Gene Full Name

sodium voltage-gated channel alpha subunit 11

Chromosome

3p22.2

Zygosity of Responsible Variant

Heterozygous

Variant Mechanism

Toxic Gain of Function (GoF)

Details

Mechanistic basis:
Overactivity

Confidence:
High

Prediction:
The literature predicts a gain of function in HSAN-7 at the level of a single channel: heterozygous de novo SCN11A missense variants, classically p.Leu811Pro, shift Nav1.9 toward a persistently open state, and the resulting standing inward sodium current holds nociceptors chronically depolarized. Sodium channels needed for the action potential upstroke sit inactivated at that membrane potential, so the neuron cannot fire, and the clinical result is congenital insensitivity to pain with self-mutilation and slow-healing injuries. Variants that lower Nav1.9 activity instead track with painful small-fiber phenotypes.

Rationale:
Persistent current, not reduced excitability, is the primary lesion, and the paradox of a hyperactive channel silencing its neuron resolves once depolarization block is taken into account. The mutant channel is overactive in heterologous expression on its own terms, with no requirement that it act on the wild-type allele, and the opposite pain phenotype at the same gene shows that direction of effect matters more than dose.

ClinVar Pathogenic Variants

View SCN11A ClinVar Variants

ClinGen Curation

View SCN11A ClinGen Curation

HSAN-7 OMIM Entry

HSAN-7 OMIM

SCN11A OMIM Entry

SCN11A OMIM