ClinVar

Description

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on LRP5 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1043257). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 178 of the LRP5 protein (p.Arg178Gln). This variant is present in population databases (rs183377804, gnomAD 0.006%). This missense change has been observed in individuals with clinical features of autosomal recessive osteoporosis-pseudoglioma syndrome and/or clinical features of autosomal dominant osteoporosis with retinopathy (PMID: 33939331; Invitae).