Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000481349 | SCV000574401 | uncertain significance | not provided | 2017-03-23 | criteria provided, single submitter | clinical testing | The C142S variant has been reported previously in a patient with X-linked hypophosphatemic rickets (Lo et al., 2006) with limited evidence for pathogenicity. C142S is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). It 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. Additionally, missense variants at the same (C142F/R) and in nearby residues (L138P) have 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. However, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. |
| Labcorp Genetics |
RCV000481349 | SCV001373535 | pathogenic | not provided | 2022-11-29 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys142 amino acid residue in PHEX. Other variant(s) that disrupt this residue have been observed in individuals with PHEX-related conditions (PMID: 10439971, 25086671), which suggests that this may be a clinically significant amino acid residue. 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: 424579). This missense change has been observed in individual(s) with clinical features of hhypophosphatemic rickets (PMID: 32253725). This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 142 of the PHEX protein (p.Cys142Ser). |