ClinVar

Description

This variant is not present in population databases (ExAC no frequency). 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. This variant disrupts the p.Asp646 amino acid residue in PHEX. Other variant(s) that disrupt this residue have been observed in individuals with PHEX-related conditions (PMID: 21050253, Invitae), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in an individuals with hypophosphatemia (Invitae). ClinVar contains an entry for this variant (Variation ID: 438510). This sequence change replaces aspartic acid with histidine at codon 646 of the PHEX protein (p.Asp646His). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and histidine.