CMT2DD

Genetic Context

HGNC-Approved Gene Symbol

ATP1A1

Gene Full Name

Atpase Na+/k+ Transporting Subunit Alpha 1

HGNC Gene Alias(es)

ATPase, Na+/K+ Transporting, Alpha 1 Polypeptide

Chromosome

1p13.1

Zygosity of Responsible Variant

Heterozygous

Mitochondrial Involvement

No

Variant Mechanism

Toxic Gain of Function (GoF)

Details

Mechanistic basis:
Neomorphic

Confidence:
Medium

Prediction:
The literature predicts a gain-of-function mechanism for CMT2DD: functional work on these dominant ATP1A1 α1 Na/K-ATPase variants (Clausen et al. 2023) concludes that disease requires a malfunctioning product expressed from one allele and is not haploinsufficiency, supporting an aberrant neomorphic activity of the mutant pump rather than simple loss of a copy. The evidence is from limited functional studies, holding confidence at medium.

Rationale:
Dominant ATP1A1 CMT2DD missense variants act through a neomorphic gain of function, most plausibly an aberrant cation leak through the mutant Na/K-ATPase rather than disruption of the wild-type pump, consistent with the finding that a malfunctioning product is required and that this is not haploinsufficiency. The leak-versus-interference distinction is unresolved on limited data, holding confidence at medium.

ClinVar Pathogenic Variants

View CMT2DD ClinVar Variants

ClinGen Curation

View ATP1A1 ClinGen Curation

CMT2DD OMIM Entry

CMT2DD OMIM

ATP1A1 OMIM Entry

ATP1A1 OMIM