Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000481780 | SCV000570580 | likely pathogenic | not provided | 2017-02-10 | criteria provided, single submitter | clinical testing | The G572S variant in the PHEX gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). G572S is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in the same codon (G572D) has been reported in the Human Gene Mutation Database in association with X-linked hypophosphatemic rickets (Stenson et al., 2014). In addition, other missense variants in the same codon (G572R/V) have been observed at GeneDx, supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. |
| Invitae | RCV000481780 | SCV001374481 | pathogenic | not provided | 2021-08-17 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine with serine at codon 572 of the PHEX protein (p.Gly572Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with hypophosphatemic rickets (Invitae). ClinVar contains an entry for this variant (Variation ID: 421390). 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 disrupts the p.Gly572 amino acid residue in PHEX. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16055933, 11502829, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |