C-type natriuretic peptide (CNP) is critically involved in endochondral bone growth. Variants in the genes encoding CNP or its cGMP-forming receptor (natriuretic peptide receptor-B (NPR-B), gene NPR2) cause monogenic growth disorders. Here we describe a novel gain-of-function variant of NPR-B associated with tall stature and macrodactyly of the great toes (epiphyseal chondrodysplasia, Miura type).History and clinical characteristics of three family members were collected. NPR2 was selected for sequencing. Skin fibroblasts and transfected HEK-293 cells were used to compare mutant versus wild-type NPR-B activities. Homology modelling was applied to understand the molecular consequences of the variant.Mother's height was +2.77 SDS. The heights of her two daughters were +1.96 SDS at 7 years and +1.30 SDS at 4 years of age. Skeletal surveys showed macrodactyly of the great toes and pseudo-epiphyses of the mid- and proximal phalanges. Sequencing identified a novel heterozygous variant c.1444_1449delATGCTG in exon-8 of NPR2, predicted to result in deletion of two amino acids Met482-Leu483 within the sub-membrane region of NPR-B. In proband´s skin fibroblasts, basal cGMP levels and CNP-stimulated cGMP production were markedly increased as compared to controls. Consistently, assays with transfected HEK-293 cells showed markedly augmented baseline and ligand-dependent activity of mutant NPR-B.We report the second activating variant within the intracellular sub-membrane region of NPR-B resulting in tall stature and macrodactyly. Our functional and modelling studies suggest that this domain plays a critical role in the baseline conformation and ligand-dependent structural rearrangement of NPR-B required for cGMP production.