Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000413461 | SCV000491263 | likely pathogenic | not provided | 2016-07-19 | criteria provided, single submitter | clinical testing | This variant has been previously published in association with X-linked hypophosphatemic rickets (Filisetti et al., 1999; Quinlan et al., 2012) with limited data to fully support pathogenicity. The W456C 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. The W456C variant 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 a nearby residue (L450P) has also been reported in the Human Gene Mutation Database in association with 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. |
| Labcorp Genetics |
RCV000413461 | SCV001396645 | pathogenic | not provided | 2022-01-04 | criteria provided, single submitter | clinical testing | This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 456 of the PHEX protein (p.Trp456Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypophosphatemia (PMID: 10439971, 22101457, 29460029; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 287635). 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. This variant disrupts the p.Trp456 amino acid residue in PHEX. Other variant(s) that disrupt this residue have been observed in individuals with PHEX-related conditions (PMID: 29460029), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. |
| Eurofins Ntd Llc |
RCV000413461 | SCV000341459 | uncertain significance | not provided | 2016-06-01 | flagged submission | clinical testing |