Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000419789 | SCV000514110 | likely pathogenic | not provided | 2016-12-20 | criteria provided, single submitter | clinical testing | A novel G579E variant that is likely pathogenic was identified in the PHEX gene. It has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. G579E 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. Missense variants in the same residue (G579R/V) and in nearby residues (H580P, F582S, H584P) have been reported in the Human Gene Mutation Database in association with X-linked hypophosphatemic rickets (Stenson et al., 2014), 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 | RCV000419789 | SCV004412443 | likely pathogenic | not provided | 2022-11-14 | criteria provided, single submitter | clinical testing | 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.Gly579 amino acid residue in PHEX. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9097956, 9199930, 11468271, 18625346, 29858904). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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) performed at Invitae indicates that this missense variant is expected to disrupt PHEX protein function. ClinVar contains an entry for this variant (Variation ID: 378359). This missense change has been observed in individual(s) with clinical features of hypophosphatemia (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 579 of the PHEX protein (p.Gly579Glu). |