|Likely Pathogenic Variant for Hypochondroplasia|
|| common in clinvar
rs77722678, also known as c.1619A>G, p.Asn540Ser and N540S, represents a rare mutation in the FGFR3 gene on chromosome 4. The rare (minor) allele has been associated with a form of hypochondroplasia, inherited in an autosomal dominant manner.
[PMID 10777366] Mortier G, et al. (2000) - The p.N540S alteration was seen in a family with a clinical diagnosis of hypochondroplasia. The daughter had short stature, prominent forehead, low nasal bridge, anteroposteriorly flattened thorax, and lumbar hyperlordosis. Skeletal examination showed mild shortening of the tubular bones, minimal increase in lumbar interpedicular distance, and anteroposterior shortening of the lumbar. The father was short with macrocephaly and a prominent forehead, low nasal bridge, muscular build, and broad thorax. He had the same skeletal findings as his daughter, but also presented with long proximal portion of the fibula and remarkably short femoral necks.
Domain Information - The p.N540 amino acid is located in the molecular break region of the kinase domain and it is part of a complex loop/hinge region. It is solvent-exposed and interacts with charged residues. The role of the kinase domain is to stabilize the inactive state over the active state of the protein by forming a dynamic hydrogen bond network. A loss of the dynamic network of the hydrogen bonds results in over-activation of the kinase which is correlated with hypochondroplasia [PMID 23972473] [PMID 26220993]. The known likely pathogenic alteration, p.N540K, disrupts the hydrogen bonding network as does the p.N540S alteration. Other variants in this region that result in activating the protein/gain-of-function have been shown to result in the spectrum of hypochondraplasia [PMID 23972473] [PMID 26220993]. Even a mild disruption of this region corresponds to pathogenicity as seen in the likely pathogenic alteration, p.I538V [PMID 9222758].